U.S. patent application number 12/200191 was filed with the patent office on 2011-02-17 for gabapentin for the treatment of overactive bladder, stress incontinence and bph.
This patent application is currently assigned to Pfizer Inc. Invention is credited to Charles Price Taylor, JR., Andrew John Thorpe, Simon Lemprier Westbrook, David Juergen Wustrow.
Application Number | 20110039899 12/200191 |
Document ID | / |
Family ID | 32966585 |
Filed Date | 2011-02-17 |
United States Patent
Application |
20110039899 |
Kind Code |
A1 |
Taylor, JR.; Charles Price ;
et al. |
February 17, 2011 |
Gabapentin for the Treatment of Overactive Bladder, Stress
Incontinence and BPH
Abstract
Use of an alpha-2-delta ligand, or a pharmaceutically acceptable
derivative thereof, for the manufacture of a medicament for the
treatment of LUTS, other than urinary incontinence, associated with
OAB and/or BPH.
Inventors: |
Taylor, JR.; Charles Price;
(Ann Arbor, MI) ; Thorpe; Andrew John; (Ann Arbor,
MI) ; Westbrook; Simon Lemprier; (Sandwich, GB)
; Wustrow; David Juergen; (Ann Arbor, MI) |
Correspondence
Address: |
PFIZER INC.;PATENT DEPARTMENT
Bld 114 M/S 9114, EASTERN POINT ROAD
GROTON
CT
06340
US
|
Assignee: |
Pfizer Inc
|
Family ID: |
32966585 |
Appl. No.: |
12/200191 |
Filed: |
August 28, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10732613 |
Dec 10, 2003 |
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12200191 |
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60433491 |
Dec 13, 2002 |
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60454074 |
Mar 12, 2003 |
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Current U.S.
Class: |
514/364 ;
514/381; 514/423; 514/561 |
Current CPC
Class: |
A61K 31/18 20130101;
A61K 31/662 20130101; A61K 31/4015 20130101; A61K 31/41 20130101;
A61K 31/16 20130101; A61K 31/197 20130101; A61K 31/20 20130101;
A61P 13/00 20180101; A61K 31/198 20130101; A61K 45/06 20130101;
A61K 31/4245 20130101; A61K 31/185 20130101; A61K 31/433 20130101;
A61K 31/401 20130101; A61K 31/195 20130101 |
Class at
Publication: |
514/364 ;
514/561; 514/381; 514/423 |
International
Class: |
A61K 31/4245 20060101
A61K031/4245; A61K 31/195 20060101 A61K031/195; A61K 31/41 20060101
A61K031/41; A61K 31/40 20060101 A61K031/40; A61P 13/00 20060101
A61P013/00 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 5, 2003 |
GB |
0302657.2 |
Claims
1. A method of treating LUTS, other than urinary incontinence,
associated with OAB and/or BPH comprising administering an
alpha-2-delta ligand, or a pharmaceutically acceptable salt or
solvate thereof, to a patient in need of such treatment.
2. The method of claim 1, wherein the LUTS is associated with
BPH.
3. The method of claim 1, wherein the LUTS is associated with
OAB.
4. The method of claim 3, wherein the OAB is OAB dry.
5. The method of claim 1, wherein the LUTS is frequency.
6. The method of claim 1, wherein the LUTS is nocturia.
7. The method of claim 1, wherein the alpha-2-delta ligand is
selected from the group consisting of: ##STR00025## ##STR00026##
##STR00027## ##STR00028## ##STR00029## or a pharmaceutically
acceptable salt or solvate thereof; wherein R.sup.1 and R.sup.2 are
each independently selected from H, straight or branched alkyl of
1-6 carbon atoms, cycloalkyl of from 3-6 carbon atoms, phenyl and
benzyl, subject to the proviso that, except in the case of a
tricyclooctane compound of formula (XVIII), R.sup.1 and R.sup.2 are
not simultaneously hydrogen; or it is selected from the group
consisting of: ##STR00030## or a pharmaceutically acceptable salt
or solvate thereof.
8. The method of claim 7 wherein the alpha-2-delta ligand is
gabapentin (I) ##STR00031## or a pharmaceutically acceptable salt
or solvate thereof.
9. The method of claim 7 wherein the alpha-2-delta ligand is
pregabalin (II) ##STR00032## or a pharmaceutically acceptable salt
or solvate thereof.
10. The method of claim 1 wherein the alpha-2-delta ligand is
(1.alpha.,3.alpha.,5.alpha.)(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acet-
ic acid (III') ##STR00033## or a pharmaceutically acceptable salt
or solvate thereof.
11. The method of claim 7, wherein the alpha-2-delta ligand is
4-(3-fluoro-benzyl)-pyrrolidine-2-carboxylic acid (XXXV)
##STR00034## or a pharmaceutically acceptable salt or solvate
thereof.
12. The method of claim 7, wherein the alpha-2-delta ligand is a
compound of formula (XXX) as defined therein, or a pharmaceutically
acceptable salt or solvate thereof.
13. A method of treating LUTS associated with OAB and/or BPH
comprising administering to a patient in need of such treatment a
combination of an alpha-2-delta ligand and a compound selected from
the group consisting of: (i) a PDEV inhibitory compound; and (ii) a
muscarinic antagonist; or pharmaceutically acceptable salts or
solvates thereof.
14. The method of claim 13, wherein the alpha-2-delta ligand is
administered in combination with a muscarinic antagonist.
15. The method of claim 14, wherein the muscarinic antagonist is
tolterodine.
16. The method of claim 13, wherein the LUTS is other than urinary
incontinence.
17. The method of claim 13, wherein the LUTS is associated with
BPH.
18. The method of claim 13, wherein the LUTS is associated with
OAB.
19. The method of claim 18, wherein the OAB is OAB dry.
20. The method of claim 13, wherein the LUTS is frequency.
21. The method of claim 13, wherein the LUTS is nocturia.
22. The method of claim 13, wherein the alpha-2-delta ligand is
selected from the group consisting of: ##STR00035## ##STR00036##
##STR00037## ##STR00038## ##STR00039## or a pharmaceutically
acceptable salt or solvate thereof; wherein R.sup.1 and R.sup.2 are
each independently selected from H, straight or branched alkyl of
1-6 carbon atoms, cycloalkyl of from 3-6 carbon atoms, phenyl and
benzyl, subject to the proviso that, except in the case of a
tricyclooctane compound of formula (XVIII), R.sup.1 and R.sup.2 are
not simultaneously hydrogen; or it is selected from the group
consisting of: ##STR00040## or a pharmaceutically acceptable salt
or solvate thereof.
23. The method of claim 22 wherein the alpha-2-delta ligand is
gabapentin (I) ##STR00041## or a pharmaceutically acceptable salt
or solvate thereof.
24. The method of claim 22 wherein the alpha-2-delta ligand is
pregabalin (II) ##STR00042## or a pharmaceutically acceptable salt
or solvate thereof.
25. The method of claim 13 wherein the alpha-2-delta ligand is
(1.alpha.,3.alpha.,5.alpha.)(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acet-
ic acid (III') ##STR00043## or a pharmaceutically acceptable salt
or solvate thereof.
26. The method of claim 22, wherein the alpha-2-delta ligand is
4-(3-fluoro-benzyl)-pyrrolidine-2-carboxylic acid (XXXV)
##STR00044## or a pharmaceutically acceptable salt or solvate
thereof.
27. The method of claim 22, wherein the alpha-2-delta ligand is a
compound of formula (XXX) as defined therein, or a pharmaceutically
acceptable salt or solvate thereof.
28. A pharmaceutical composition containing an alpha-2-delta ligand
and a compound selected from the group consisting of: (i) a PDEV
inhibitor; and (ii) a muscarinic antagonist; or a pharmaceutically
acceptable salt or solvate thereof and a pharmaceutically
acceptable carrier.
29. The pharmaceutical composition of claim 28, wherein the
alpha-2-delta ligand is selected from the group consisting of:
##STR00045## ##STR00046## ##STR00047## ##STR00048## ##STR00049## or
a pharmaceutically acceptable salt or solvate thereof; wherein
R.sup.1 and R.sup.2 are each independently selected from H,
straight or branched alkyl of 1-6 carbon atoms, cycloalkyl of from
3-6 carbon atoms, phenyl and benzyl, subject to the proviso that,
except in the case of a tricyclooctane compound of formula (XVIII),
R.sup.1 and R.sup.2 are not simultaneously hydrogen; or it is
selected from the group consisting of: ##STR00050## or a
pharmaceutically acceptable salt or solvate thereof, and is in
combination with a muscarinic antagonist.
30. The pharmaceutical composition of claim 29, wherein the
muscarinic antagonist is tolterodine.
Description
[0001] This application claims priority to U.S. Ser. No.
10/732,613, filed Dec. 10, 2003, which claims priority to U.S.
Provisional Application Ser. No. 60/433,491, filed Dec. 13, 2002,
United Kingdom Patent Application, filed Feb. 5, 2003, and U.S.
Provisional Application Ser. No. 60/454,074, filed Mar. 12,
2003.
FIELD OF THE INVENTION
[0002] This invention relates to a new use of alpha-2-delta ligands
and their pharmaceutically acceptable derivatives. In particular it
relates to a new use of gabapentin and pregabalin.
[0003] Lower urinary tract symptoms (LUTS) comprise three groups of
symptoms, which are irritative, obstructive and post micturition
symptoms. Irritative symptoms comprise urgency, frequency and
nocturia, which can be associated with: overactive bladder (OAB)
and benign prostatic hyperplasia (BPH).
[0004] Over Active Bladder (OAB) is defined as urgency, with or
without urge incontinence, usually with frequency and nocturia
[Abrams et al., Neurourology and Urodynamics 21:167-178 (2002)].
Prevalence of OAB in men and women is similar, with approximately
16% of the population of the USA suffering from the condition
[Stewart et al, Prevalence of Overactive Bladder in the United
States: Results from the NOBLE Program; Abstract Presented at the
2.sup.nd International Consultation on Incontinence, July 2001,
Paris, France].
[0005] The terms OAB Wet and OAB Dry describe OAB patients with or
without urinary incontinence respectively. Until recently, the
cardinal symptom of OAB was believed to be urinary incontinence.
However, with the advent of the new terms this is clearly not
meaningful for the large number of sufferers who are not
incontinent (i.e. OAB Dry patients). Thus, a recent study from
Liberman et al [Health Related Quality of Life Among Adults with
Symptoms of Overactive Bladder: Results From A US Community-Based
Survey; Urology 57(6), 1044-1050, 2001] examined the impact of all
OAB symptoms on the quality of life of a community-based sample of
the US population. This study demonstrated that individuals
suffering from OAB without any demonstrable loss of urine have an
impaired quality of life when compared with controls.
[0006] BPH is a chronically progressive disease that can lead to
complications such as acute urinary retention, recurrent urinary
tract infections, bladder stones and renal dysfunction. The
prevalence and average severity of LUTS associated with BPH in men
increases with age.
[0007] BPH leads to an increase in prostate volume, creating
urethral and bladder outflow obstruction as well as secondary
changes in bladder function. The effects of this are manifested by
both storage (irritative) and voiding (obstructive) symptoms.
[0008] Alpha-2-delta ligands have been described for a number of
indications. The best known alpha-2-delta ligand, gabapentin (I),
known as Neurontin.RTM., 1-(aminomethyl)-cyclohexylacetic acid, was
first described in the patent literature in the patent family
comprising U.S. Pat. No. 4,024,175.
##STR00001##
[0009] The compound is approved for the treatment of epilepsy and
neuropathic pain.
[0010] A second alpha-2-delta ligand, pregabalin (II),
(S)-(+)-4-amino-3-(2-methylpropyl)butanoic acid, is described in
European patent application publication number EP641330 as an
anti-convulsant treatment useful in the treatment of epilepsy and
in EP0934061 for the treatment of pain.
##STR00002##
[0011] More recently, International Patent Publication Number WO
02/085839, describes alpha-2-delta ligands of the following
formulae, for use in the treatment of a number of indications,
including pain:
##STR00003## ##STR00004## ##STR00005##
wherein R.sup.1 and R.sup.2 are each independently selected from H,
straight or branched alkyl of 1-6 carbon atoms, cycloalkyl of from
3-6 carbon atoms, phenyl and benzyl, subject to the proviso that,
except in the case of a tricyclooctane compound of formula (XVIII),
R.sup.1 and R.sup.2 are not simultaneously hydrogen.
[0012] Further examples of alpha-2-delta ligands are the compounds
depicted below:
##STR00006##
Useful cyclic alpha-2-delta ligands of the present invention are
illustrated by the following formula (I):
##STR00007##
wherein X is a carboxylic acid or carboxylic acid bioisostere;
[0013] n is 0, 1 or 2; and
[0014] R.sup.1, R.sup.1a, R.sup.2, R.sup.2a, R.sup.3, R.sup.3a,
R.sup.4 and R.sup.4a are independently selected from H and
C.sub.1-C.sub.6 alkyl, or
[0015] R.sup.1 and R.sup.2 or R.sup.2 and R.sup.3 are taken
together to form a C.sub.3-C.sub.7 cycloalkyl ring, which is
optionally substituted with one or two substituents selected from
C.sub.1-C.sub.6 alkyl, or a pharmaceutically acceptable salt
thereof.
[0016] In formula (I), suitably, R.sup.1, R.sup.1a, R.sup.2a,
R.sup.3a, R.sup.4 and R.sup.4a are H and R.sup.2 and R.sup.3 are
independently selected from H and methyl, or R.sup.1a, R.sup.2a,
R.sup.3a and R.sup.4a are H and R.sup.1 and R.sup.2 or R.sup.2 and
R.sup.3 are taken together to form a C.sub.3-C.sub.7 cycloalkyl
ring, which is optionally substituted with one or two methyl
substituents. A suitable carboxylic acid bioisostere is selected
from tetrazolyl and oxadiazolonyl. X is preferably a carboxylic
acid.
[0017] In formula (I), preferably, R.sup.1, R.sup.1, R.sup.2a,
R.sup.3a, R.sup.4 and R.sup.4a are H and R.sup.2 and R.sup.3 are
independently selected from H and methyl, or R.sup.1a, R.sup.2a,
R.sup.3a and R.sup.4a are H and R.sup.1 and R.sup.2 or R.sup.2 and
R.sup.3 are taken together to form a C.sub.4-C.sub.5 cycloalkyl
ring, or, when n is 0, R.sup.1, R.sup.1a, R.sup.2a, R.sup.3a,
R.sup.4 and R.sup.4a are H and R.sup.2 and R.sup.3 form a
cyclopentyl ring, or, when n is 1, R.sup.1, R.sup.1a, R.sup.2a,
R.sup.3a, R.sup.4 and R.sup.4a are H and R.sup.2 and R.sup.3 are
both methyl or R.sup.1, R.sup.1a, R.sup.2a, R.sup.3a, R.sup.4 and
R.sup.4a are H and R.sup.2 and R.sup.3 form a cyclobutyl ring, or,
when n is 2, R.sup.1, R.sup.1a, R.sup.2, R.sup.2a, R.sup.3,
R.sup.3a, R.sup.4 and R.sup.4a are H, or, n is 0, R.sup.1,
R.sup.1a, R.sup.2a, R.sup.3a, R.sup.4 and R.sup.4a are H and
R.sup.2 and R.sup.3 form a cyclopentyl ring.
[0018] Useful acyclic alpha-2-delta ligands of the present
invention are illustrated by the following formula (II):
##STR00008##
[0019] wherein:
[0020] n is 0 or 1, R.sup.1 is hydrogen or (C.sub.1-C.sub.6)alkyl;
R.sup.2 is hydrogen or (C.sub.1-C.sub.6)alkyl; R.sup.3 is hydrogen
or (C.sub.1-C.sub.6)alkyl; R.sup.4 is hydrogen or
(C.sub.1-C.sub.6)alkyl; R.sup.5 is hydrogen or
(C.sub.1-C.sub.6)alkyl and R.sup.2 is hydrogen or
(C.sub.1-C.sub.6)alkyl, or a pharmaceutically acceptable salt
thereof.
[0021] According to formula (II), suitably R.sup.1 is
C.sub.1-C.sub.6 alkyl, R.sup.2 is methyl, R.sup.3-- R.sup.6 are
hydrogen and n is 0 or 1. More suitably R.sup.1 is methyl, ethyl,
n-propyl or n-butyl, R.sup.2 is methyl, R.sup.3-- R.sup.6 are
hydrogen and n is 0 or 1. When R.sup.2 is methyl, R.sup.3-- R.sup.6
are hydrogen and n is 0, R.sup.1 is suitably ethyl, n-propyl or
n-butyl. When R.sup.2 is methyl, R.sup.3-- R.sup.6 are hydrogen and
n is 1, R.sup.1 is suitably methyl or n-propyl. Compounds of
formula (II) are suitably in the 3S,5R configuration.
[0022] Examples of alpha-2-delta ligands for use with the present
invention are those compounds generally or specifically disclosed
in U.S. Pat. No. 4,024,175, particularly gabapentin, EP,641330,
particularly pregabalin, U.S. Pat. No. 5,563,175, WO 9733858, WO
9733859, WO 9931057, WO 9931074, WO 9729101, WO 02085839,
particularly
[(1R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, WO
9931075, particularly
3-(1-aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one and
C-[1-(1H-tetrazol-5-ylmethyl)-cycloheptyl]-methylamine, WO 9921824,
particularly
(3S,4S)-(1-aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid, WO
0190052, WO 0128978, particularly
(1.alpha.,3.alpha.,5.alpha.)(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acet-
ic acid, EP 0641330, WO 9817627, WO 0076958, particularly
(3S,5R)-3-aminomethyl-5-methyl-octanoic acid, PCT/IB03/00976,
particularly (3S,5R)-3-amino-5-methyl-heptanoic acid,
(3S,5R)-3-amino-5-methyl-nonanoic acid and
(3S,5R)-3-Amino-5-methyl-octanoic acid, EP 1178034, EP 1201240, WO
9931074, WO 03000642, WO 0222568, WO 0230871, WO 0230881, WO
02100392, WO 02100347, WO 0242414, WO 0232736 and WO 0228881 or
pharmaceutically acceptable salts thereof, all of which are
incorporated herein by reference.
[0023] Preferred alpha-2-delta ligands of the present invention
include: gabapentin, pregabalin,
[(1R,5R,6S)-6-(Aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid,
3-(1-aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one,
C-[1-(1H-tetrazol-5-ylmethyl)-cycloheptyl]-methylamine,
(3S,4S)-(1-aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid,
(1.alpha.,3.alpha.,5.alpha.)(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acet-
ic acid, (3S,5R)-3-aminomethyl-5-methyl-octanoic acid,
(3S,5R)-3-amino-5-methyl-heptanoic acid,
(3S,5R)-3-amino-5-methyl-nonanoic acid and
(3S,5R)-3-Amino-5-methyl-octanoic acid, or pharmaceutically
acceptable salts thereof. Particularly preferred alpha-2-delta
ligands of the present invention are selected from gabapentin,
pregabalin and
(1.alpha.,3.alpha.,5.alpha.)(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acet-
ic acid, or pharmaceutically acceptable salts thereof.
[0024] WO 00/01135 describes the use of analogs of glutamic acid
and gamma-aminobutyric acid as being useful in treating
incontinence.
[0025] Surprisingly, it has been found that alpha-2-delta ligands,
such as those described above, are useful in the treatment of LUTS,
other than urinary incontinence, associated with OAB and/or BPH.
More particularly, it has been found that alpha-2-delta ligands are
useful in treating the frequency aspect of LUTS associated with OAB
and/or BPH. This finding is surprising because it could not have
been predicted that a compound known to be useful in the treatment
of urinary incontinence (i.e., the unwanted and often unconscious
leaking of urine due to problems with muscular control) would be
able to reduce the frequency symptoms endured by sufferers of OAB
and BPH.
[0026] Thus, in accordance with the present invention there is
provided the use of an alpha-2-delta ligand, or a pharmaceutically
acceptable salt or solvate thereof, for the treatment of LUTS,
other than urinary incontinence, associated with OAB and/or
BPH.
[0027] Preferably the LUTS is frequency. Preferably, the LUTS is
associated with BPH. Preferably, when the LUTS is associated with
OAB, the OAB is OAB Dry.
[0028] Preferably the alpha-2-delta-1-ligand is selected from:
##STR00009## ##STR00010## ##STR00011## ##STR00012##
##STR00013##
or a pharmaceutically acceptable salt or solvate thereof, wherein
R.sup.1 and R.sup.2 are each independently selected from H,
straight or branched alkyl of 1-6 carbon atoms, cycloalkyl of from
3-6 carbon atoms, phenyl and benzyl, subject to the proviso that,
except in the case of a tricyclooctane compound of formula (XVIII),
R.sup.1 and R.sup.2 are not simultaneously hydrogen; or it is
selected from
##STR00014##
or a pharmaceutically acceptable salt or solvate thereof.
[0029] More preferably the alpha-2-delta ligand is gabapentin (I),
pregabalin (II) or
(1.alpha.,3.alpha.,5.alpha.)(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acet-
ic acid (III')
##STR00015##
or a pharmaceutically acceptable salt or solvate thereof.
[0030] The alpha-2-delta ligand, or pharmaceutically acceptable
derivative thereof, can be administered alone or in any convenient
pharmaceutical presentation. Oral administration is preferred. In
the present indication, a suitable dosage of the alpha-2-delta
ligand, or of the active moiety in a pharmaceutically acceptable
derivative thereof, is from about 5 to 50 mg/kg of body weight, and
preferably about 0.1 to 200 mg/kg.
[0031] The invention further provides a method of treating LUTS,
other than urinary incontinence, associated with OAB and/or BPH
comprising administering an alpha-2-delta ligand, or
pharmaceutically acceptable salt or solvate thereof, to a patient
in need of such treatment.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
[0032] FIG. 1 is a graph demonstrating that the interval between
voiding events was increased in response to gabapentin relative to
corresponding control periods.
[0033] FIG. 2 is a graph demonstrating that gabapentin at 60 mg/kg
s/c significantly decreased (P<0.05) micturition interval and
hence increased bladder capacity.
[0034] FIG. 3 is a graph demonstrating that average bladder
pressure during the filling stages of the micturition cycle were
significantly decreased (P<0.05) in response to Gabapentin
relative to corresponding control periods.
[0035] Alpha-2-delta ligands, particularly the compounds described
above, may be used in combination with other compounds. For
example, they may be used in combination with .alpha.1-Adrenergic
antagonists.
[0036] Thus, a further aspect of the present invention is the use
of a combination of an alpha-2-delta ligand and an
.alpha.1-adrenergic antagonist, or pharmaceutically acceptable
salts or solvates thereof, for the manufacture of a medicament for
the treatment of LUTS, associated with OAB and/or BPH.
[0037] Still further there is provided a product containing an
alpha-2-delta ligand and an .alpha.1-adrenergic antagonist, or
pharmaceutically acceptable salts or solvates thereof, as a
combined preparation for simultaneous, separate or sequential use
in the treatment of LUTS associated with OAB and/or BPH.
[0038] Preferably, the LUTS is other than urinary incontinence.
More preferably, the LUTS is frequency. Preferably the LUTS is
associated with BPH. Preferably, when the LUTS is associated with
OAB, it is OAB dry.
[0039] .alpha..sub.1-Adrenergic receptor antagonists useful for
combining with alpha-2-delta ligands include, but are not limited
to: [0040] (i) terazosin (U.S. Pat. No. 4,026,894); [0041] (ii)
doxazosin (U.S. Pat. No. 4,188,390); [0042] (iii) prazosin (U.S.
Pat. No. 3,511,836); [0043] (iv) bunazosin (U.S. Pat. No.
3,920,636); [0044] (v) alfuzosin (U.S. Pat. No. 4,315,007); [0045]
(vi) naftopidil (U.S. Pat. No. 3,997,666); [0046] (vii) tamsulosin
(U.S. Pat. No. 4,703,063); [0047] (viii) silodosin (U.S. Pat. No.
5,387,603); or [0048] (ix) the compounds disclosed in International
Patent Application Publication No. WO 98/30560 (particularly
example 19 and its mesylate salt).
[0049] The contents of the patent applications and in particular
the general formulae of the therapeutically active compounds of the
claims and exemplified compounds therein are incorporated herein in
their entirety by reference thereto.
[0050] Alternatively, alpha-2-delta ligands may be used in
combination with a compound which shows NRI and/or SRI activity.
Thus a further aspect of the present invention is the use of a
combination of an alpha-2-delta ligand and a compound showing NRI
and/or SRI activity, or pharmaceutically acceptable salts or
solvates thereof, for the manufacture of a medicament for the
treatment of LUTS associated with OAB and/or BPH.
[0051] Still further there is provided a product containing an
alpha-2-delta ligand and a compound showing NRI and/or SRI
activity, or pharmaceutically acceptable salts or solvates thereof,
as a combined preparation for simultaneous, separate or sequential
use in the treatment of LUTS associated with OAB and/or BPH.
[0052] Preferably, the LUTS is other than urinary incontinence.
More preferably, the LUTS is frequency. Preferably the LUTS is
associated with BPH. Preferably, when the LUTS is associated with
OAB, the OAB is OAB dry.
[0053] Compounds having NRI and/or SRI activity which are useful
for use in the present invention include, but are not limited to,
the compounds below: [0054] (i) fluoxetine, fluvoxamine,
paroxetine, sertraline, citalopram, vanlafaxine, nefazodone,
trazodone, duloxetine and reboxetine (in both racemic and
enantiomerically pure forms, e.g. S,S-reboxetine); and [0055] (ii)
the compounds disclosed in European Patent Publication No's.
1220831 and 1154984, U.S. Pat. No. 4,018,830, International Patent
Publication No. WO 97/17325, U.S. Pat. Nos. 5,190,965, 5,430,063,
4,161,529 and U.S. Provisional Application No. 60/121,313.
[0056] The contents of the patent applications and in particular
the general formulae of the therapeutically active compounds of the
claims and exemplified compounds therein are incorporated herein in
their entirety by reference thereto.
[0057] Alternatively, alpha-2-delta ligands may be used in
combination with a HMG Co-A reductase inhibitor. Thus a further
aspect of the present invention is the use of a combination of an
alpha-2-delta ligand and a HMG Co-A reductase inhibitor, or a
pharmaceutically acceptable salt or solvate thereof, for the
manufacture of a medicament for the treatment of LUTS associated
with OAB and/or BPH.
[0058] Still further there is provided a product containing an
alpha-2-delta ligand and a HMG Co-A Reductase inhibitor, or a
pharmaceutically acceptable salt or solvate thereof, as a combined
preparation for simultaneous, separate or sequential use in the
treatment of LUTS associated with OAB and/or BPH.
[0059] Preferably, the LUTS is other than urinary incontinence.
More preferably, the LUTS is frequency. Preferably the LUTS is
associated with BPH. Preferably, when the LUTS is associated with
OAB, the OAB is OAB dry.
[0060] HMG Co-A Reductase inhibitors useful for use in the present
invention include, but are not limited to, the compounds below:
[0061] (i) fluvastatin sodium,
[R*,S*,-(E)]-(.+-.)-7-[3-(4-fluorophenyl)-1-(1-methylethyl)-H-indol-2-yl]-
-3,5-dihydroxy-6-heptenoic acid, monosodium salt; [0062] (ii)
cerivastatin sodium,
[S-[R*,S*-(E)]-7-[4-(4-fluorophenyl)-5-methoxymethyl)-2,6-bis(1-m-
ethylethyl)-3-pyridinyl]-3,5-dihydroxy-6-heptenoate; [0063] (iii)
atorvastatin calcium, [R--(R*,R*)]-2-(4-fluorophenyl)-beta,
delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-p-
yrrole-1-heptanoic acid, calcium salt (2:1) trihydrate; [0064] (iv)
lovastatin, {S-[1-alpha(R*), 3-alpha, 7-beta, 8-beta (2S*,4S*), 8a
beta]}-1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-o-
xo-2H-pyran-2-yl)ethyl]-1-naphthalenyl-2-methylbutanoate; [0065]
(v) pravastatin sodium, 1-naphthalene-heptanoic acid,
1,2,6,7,8,8a-hexahydro-beta,
delta,6-trihydroxy-2-methyl-8-(2-methyl-1-oxobutoxy)-, monosodium
salt, {1S-[1alpha(betas*, deltas*), 2 alpha, 6 alpha, 8 beta(R*),
8a alpha]}; and [0066] (vi) simvastatin, butanoic
acid,2,2-dimethyl-1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4--
hydroxy-6-oxo-2H-pyran-2-yl)-ethyl]-1-naphthalenyl ester,
{S-[1alpha,3alpha,7beta,8beta(2S*,4S*),-8a beta]}
[0067] Alternatively, alpha-2-delta ligands may be used in
combination with PDEV inhibitors. Thus a further aspect of the
present invention is the use of a combination of an alpha-2-delta
ligand and a PDEV inhibitor, or pharmaceutically acceptable salts
or solvates thereof, for the manufacture of a medicament for the
treatment of LUTS associated with OAB and/or BPH.
[0068] Still further there is provided a product containing an
alpha-2-delta ligand and a PDEV inhibitor, or pharmaceutically
acceptable salts or solvates thereof, as a combined preparation for
simultaneous, separate or sequential use in the treatment of LUTS
associated with OAB and/or BPH.
[0069] Preferably, the LUTS is other than urinary incontinence.
More preferably, the LUTS is frequency. Preferably the LUTS is
associated with BPH. Preferably, when the LUTS is associated with
OAB, the OAB is OAB dry.
[0070] PDEV inhibitors useful for combining with alpha-2-delta
ligands include, but are not limited to: [0071] (i) The PDE5
inhibitors mentioned in International Patent Application
Publication Nos. WO 03/000691; WO 02/64590; WO 02/28865; WO
02/28859; WO 02/38563; WO 02/36593; WO 02/28858; WO 02/00657; WO
02/00656; WO 02/10166; WO 02/00658; WO 01/94347; WO 01/94345; WO
00/15639 and WO 00/15228; [0072] (ii) The PDE5 inhibitors mentioned
in U.S. Pat. Nos. 6,143,746; 6,143,747 and 6,043,252; [0073] (iii)
the pyrazolo[4,3-d]pyrimidin-7-ones disclosed in EP-A-0463756; the
pyrazolo[4,3-d]pyrimidin-7-ones disclosed in EP-A-0526004; the
pyrazolo[4,3-d]pyrimidin-7-ones disclosed in published
international patent application WO 93/06104; the isomeric
pyrazolo[3,4-d]pyrimidin-4-ones disclosed in published
international patent application WO 93/07149; the quinazolin-4-ones
disclosed in published international patent application WO
93/12095; the pyrido[3,2-d]pyrimidin-4-ones disclosed in published
international patent application WO 94/05661; the purin-6-ones
disclosed in published international patent application WO
94/00453; the pyrazolo[4,3-d]pyrimidin-7-ones disclosed in
published international patent application WO 98/49166; the
pyrazolo[4,3-d]pyrimidin-7-ones disclosed in published
international patent application WO 99/54333; the
pyrazolo[4,3-d]pyrimidin-4-ones disclosed in EP-A-0995751; the
pyrazolo[4,3-d]pyrimidin-7-ones disclosed in published
international patent application WO 00/24745; the
pyrazolo[4,3-d]pyrimidin-4-ones disclosed in EP-A-0995750; the
hexahydropyrazino [2',1':6,1]pyrido[3,4-b]indole-1,4-diones
disclosed in published international application WO 95/19978; the
pyrazolo[4,3-d]pyrimidin-4-ones disclosed in WO 00/27848; the
imidazo[5,1-f][1,2,4]triazin-ones disclosed in EP-A-1092719 and in
published international application WO 99/24433 and the bicyclic
compounds disclosed in published international application WO
93/07124; the pyrazolo[4,3-d]pyrimidin-7-ones disclosed in
published international application WO 01/27112; the
pyrazolo[4,3-d]pyrimidin-7-ones disclosed in published
international application WO 01/27113; the compounds disclosed in
EP-A-1092718 and the compounds disclosed in EP-A-1092719; the
tricyclic compounds disclosed in EP-A-1241170; the alkyl sulphone
compounds disclosed in published international application WO
02/074774; the compounds disclosed in published international
application WO 02/072586; the compounds disclosed in published
international application WO 02/079203 and the compounds disclosed
in WO 02/074312. [0074] (iv) Preferably
5-[2-ethoxy-5-(4-methyl-1-piperazinylsulphonyl)phenyl]-1-methyl-3-n-propy-
l-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (sildenafil, e.g.
as sold as Viagra.RTM.) also known as
1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5--
yl)-4-ethoxyphenyl]sulphonyl]-4-methylpiperazine (see
EP-A-0463756);
5-(2-ethoxy-5-morpholinoacetylphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H--
pyrazolo[4,3-d]pyrimidin-7-one (see EP-A-0526004);
3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-n-propoxyphenyl]-2-(pyrid-
in-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (see
WO 98/49166);
3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin--
3-yl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one
(see WO 99/54333);
(+)-3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxy-1(R)-methy-
lethoxy)pyridin-3-yl]-2-methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-o-
ne, also known as
3-ethyl-5-{5-[4-ethylpiperazin-1-ylsulphonyl]-2-([(1R)-2-methoxy-1-methyl-
ethyl]oxy)pyridin-3-yl}-2-methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-
-one (see WO 99/54333);
5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2--
methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, also
known as
1-{6-ethoxy-5-[3-ethyl-6,7-dihydro-2-(2-methoxyethyl)-7-oxo-2H-pyrazolo[4-
,3-d]pyrimidin-5-yl]-3-pyridylsulphonyl}-4-ethylpiperazine (see WO
01/27113, Example 8);
5-[2-iso-butoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-
-(1-methylpiperidin-4-yl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one
(see WO 01/27113, Example 15);
5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-phe-
nyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (see WO 01/27113,
Example 66);
5-(5-acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(1-isopropyl-3-azetidinyl)-2-
,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (see WO 01/27112,
Example 124);
5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)--
2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (see WO 01/27112,
Example 132);
(6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyph-
enyl)pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione (tadalafil,
IC-351, Cialis.RTM.), i.e. the compound of Examples 78 and 95 of WO
95/19978, as well as the compound of Examples 1, 3, 7 and 8;
2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulphonyl)-phenyl]-5-methyl-7-pro-
pyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one (vardenafil,
LEVITRA.RTM.) also known as
1-[[3-(3,4-dihydro-5-methyl-4-oxo-7-propylimidazo[5,1-f]-as-tria-
zin-2-yl)-4-ethoxyphenyl]sulphonyl]-4-ethylpiperazine, i.e. the
compound of Examples 20, 19, 337 and 336 of published international
application WO 99/24433; the compound of Example 11 of published
international application WO 93/07124 (EISAI); compounds 3 and 14
from Rotella D. P., J. Med. Chem., 2000, 43, 1257;
4-(4-chlorobenzyl)amino-6,7,8-trimethoxyquinazoline;
N-[[3-(4,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]-pyrimidin-5-
-yl)-4-propxyphenyl]sulfonyl]-1-methyl2-pyrrolidinepropanamide
["DA-8159" (Example 68 of WO 00/27848)]; and
7,8-dihydro-8-oxo-6-[2-propoxyphenyl]-1H-imidazo[4,5-g]quinazoline
and
1-[3-[1-[(4-fluorophenyl)methyl]-7,8-dihydro-8-oxo-1H-imidazo[4,5-g]quina-
zolin-6-yl]-4-propoxyphenyl]carboxamide.
(4-bromo-5-(pyridylmethylamino)-6-[3-(4-chlorophenyl)-propoxy]-3(2H)pyrid-
azinone;
1-[4-[(1,3-benzodioxol-5-ylmethyl)amiono]-6-chloro-2-quinozolinyl-
]-4-piperidine-carboxylic acid, monosodium salt;
(+)-cis-5,6a,7,9,9,9a-hexahydro-2-[4-(trifluoromethyl)-phenylmethyl-5-met-
hyl-cyclopent-4,5]imidazo[2,1-b]purin-4(3H)one; furazlocillin;
cis-2-hexyl-5-methyl-3,4,5,6a,7,8,9,9a-octahydrocyclopent[4,5]-imidazo[2,-
1-b]purin-4-one;
3-acetyl-1-(2-chlorobenzyl)-2-propylindole-6-carboxylate;
3-acetyl-1-(2-chlorobenzyl)-2-propylindole-6-carboxylate;
4-bromo-5-(3-pyridylmethylamino)-6-(3-(4-chlorophenyl)propoxy)-3-(2H)pyri-
dazinone;
I-methyl-5(5-morpholinoacetyl-2-n-propoxyphenyl)-3-n-propyl-1,6--
dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one;
1-[4-[(1,3-benzodioxol-5-ylmethyl)amino]-6-chloro-2-quinazolinyl]-4-piper-
idinecarboxylic acid, monosodium salt; Pharmaprojects No. 4516
(Glaxo Wellcome); Pharmaprojects No. 5051 (Bayer); Pharmaprojects
No. 5064 (Kyowa Hakko; see WO 96/26940); Pharmaprojects No. 5069
(Schering Plough); GF-196960 (Glaxo Wellcome); E-8010 and E-4010
(Eisai); Bay-38-3045 & 38-9456 (Bayer); FR 229934 and FR 226807
(Fujisawa); and Sch-51866.
[0075] The contents of the patent applications and journal articles
and in particular the general formulae of the therapeutically
active compounds of the claims and exemplified compounds therein
are incorporated herein in their entirety by reference thereto.
[0076] Preferably the PDEV inhibitor is selected from sildenafil,
tadalafil, vardenafil, DA-8159 and
5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2--
methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one.
[0077] Most preferably the PDE5 inhibitor is sildenafil and
pharmaceutically acceptable salts thereof. Sildenafil citrate is a
preferred salt.
[0078] Alternatively, alpha-2-delta ligands may be combined with
muscarinic antagonists. Thus, a further aspect of the present
invention is the use of a combination of an alpha-2-delta ligand
and a muscarinic antagonist, or pharmaceutically acceptable salts
or solvates thereof, for the manufacture of a medicament for the
treatment of LUTS, associated with OAB and/or BPH.
[0079] Still further there is provided a product containing an
alpha-2-delta ligand and a muscarinic antagonist, or
pharmaceutically acceptable salts or solvates thereof, as a
combined preparation for simultaneous, separate or sequential use
in the treatment of LUTS associated with OAB and/or BPH.
[0080] Preferably, the LUTS is other than urinary incontinence.
More preferably, the LUTS is frequency. Preferably, the LUTS is
associated with BPH. Preferably, when the LUTS is associated with
OAB, the OAB is OAB dry.
[0081] The muscarinic antagonist can be selective for M.sub.3
receptors or it can be non-selective, exhibiting antagonism at
M.sub.1, M.sub.2 and M.sub.3. Antagonists selective for the M.sub.3
receptor are preferred.
[0082] Muscarinic antagonists useful for combining with
alpha-2-delta ligands include, but are not limited to: [0083] (i)
atropine, fluvoxate, hyoscine, oxybutynin, tolterodine and the
compounds disclosed in International Patent Publication No. WO
89/06644, propantheline, propiverine, trospium, and the compounds
disclosed in WO 98/05641, along with the pharmaceutically
acceptable salts thereof. [0084] (ii) Especially preferred are
darifenacin, oxybutynin, tolterodine and the compounds disclosed in
WO 89/06644, and the compounds disclosed in WO 98/05641, along with
the pharmaceutically acceptable salts thereof. In particular,
tolterodine is of interest.
[0085] The contents of the patent applications and journal articles
and in particular the general formulae of the therapeutically
active compounds of the claims and exemplified compounds therein
are incorporated herein in their entirety by reference thereto.
[0086] Alternatively, alpha-2-delta ligands may be combined with
cyclooxygenase inhibitors. Thus, a further aspect of the present
invention is the use of a combination of an alpha-2-delta ligand
and a COX inhibitor, or pharmaceutically acceptable salts or
solvates thereof, for the manufacture of a medicament for the
treatment of LUTS, associated with OAB and/or BPH.
[0087] Still further there is provided a product containing an
alpha-2-delta ligand and a COX inhibitor as a combined preparation
for simultaneous, separate or sequential use in the treatment of
LUTS associated with OAB and/or BPH.
[0088] Preferably, the LUTS is other than urinary incontinence.
More preferably, the LUTS is frequency. Preferably, the LUTS is
associated with BPH. Preferably, when the LUTS is associated with
OAB it is OAB dry. Preferably the COX inhibitor is a COX2
inhibitor.
[0089] COX inhibitors useful for combining with alpha-2-delta
ligands include, but are not limited to: [0090] (i) ibuprofen,
naproxen, benoxaprofen, flurbiprofen, fenoprofen, fenbufen,
ketoprofen, indoprofen, pirprofen, carprofen, oxaprozin,
prapoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen,
tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac,
tolmetin, zomepirac, diclofenac, fenclofenec, alclofenac, ibufenac,
isoxepac, furofenac, tiopinac, zidometacin, acetyl salicylic acid,
indometacin, piroxicam, tenoxicam, nabumetone, ketorolac,
azapropazone, mefenamic acid, tolfenamic acid, diflunisal,
podophyllotoxin derivatives, acemetacin, droxicam, floctafenine,
oxyphenbutazone, phenylbutazone, proglumetacin, acemetacin,
fentiazac, clidanac, oxipinac, mefenamic acid, meclofenamic acid,
flufenamic acid, niflumic acid, flufenisal, sudoxicam, etodolac,
piprofen, salicylic acid, choline magnesium trisalicylate,
salicylate, benorylate, fentiazac, clopinac, feprazone, isoxicam
and 2-fluoro-a-methyl[1,1'-biphenyl]-4-acetic acid,
4-(nitrooxy)butyl ester (See Wenk, et al., Europ. J. Pharmacol.
453:319-324 (2002)); [0091] (ii) meloxicam, (CAS Registry No.
71125-38-7; described in U.S. Pat. No. 4,233,299), or a
pharmaceutically acceptable salt or prodrug thereof; [0092] (iii)
substituted benzopyran derivatives that are described in U.S. Pat.
No. 6,271,253. Also, benzopyran derivatives described in U.S. Pat.
Nos. 6,034,256 and 6,077,850 along with International Publication
No's. WO 98/47890 and WO 00/23433; [0093] (iv) chromene COX2
selective inhibitors described in U.S. Pat. No. 6,077,850 and U.S.
Pat. No. 6,034,256; [0094] (v) the compounds described in
International Patent Application Publication No's WO 95/30656, WO
95/30652, WO 96/38418 and WO 96/38442, and the compounds described
in European Patent Application Publication No. 799823, along with
the pharmaceutically acceptable derivatives thereof; [0095] (vi)
celecoxib (U.S. Pat. No. 5,466,823), valdecoxib (U.S. Pat. No.
5,633,272), deracoxib (U.S. Pat. No. 5,521,207), rofecoxib (U.S.
Pat. No. 5,474,995), etoricoxib (WO 98/03484), JTE-522 (Japanese
Patent Application Publication No. 9052882), or a pharmaceutically
acceptable salt or prodrug thereof; [0096] (vii) parecoxib
(described in U.S. Pat. No. 5,932,598), which is a therapeutically
effective prodrug of the tricyclic COX-2 selective inhibitor
valdecoxib (described in U.S. Pat. No. 5,633,272), in particular
sodium parecoxib; [0097] (viii) ABT-963 (described in International
Patent Application Publication No. WO 00/24719) [0098] (ix)
nimesulide (U.S. Pat. No. 3,840,597), flosulide (J. Carter, Exp.
Opin. Ther. Patents. 8(1), 21-29 (1997)), NS-398 (U.S. Pat. No.
4,885,367), SD 8381 (U.S. Pat. No. 6,034,256), BMS-347070 (U.S.
Pat. No. 6,180,651), S-2474 (European Patent Publication No.
595546) and MK-966 (U.S. Pat. No. 5,968,974); [0099] (x) The
compounds and pharmaceutically acceptable derivatives described in
U.S. Pat. No. 6,395,724, U.S. Pat. No. 6,077,868, U.S. Pat. No.
5,994,381, U.S. Pat. No. 6,362,209, U.S. Pat. No. 6,080,876, U.S.
Pat. No. 6,133,292, U.S. Pat. No. 6,369,275, U.S. Pat. No.
6,127,545, U.S. Pat. No. 6,130,334, U.S. Pat. No. 6,204,387, U.S.
Pat. No. 6,071,936, U.S. Pat. No. 6,001,843, U.S. Pat. No.
6,040,450, WO 96/03392, WO 96/24585, U.S. Pat. No. 6,340,694, U.S.
Pat. No. 6,376,519, U.S. Pat. No. 6,153,787, U.S. Pat. No.
6,046,217, U.S. Pat. No. 6,329,421, U.S. Pat. No. 6,239,137, U.S.
Pat. No. 6,136,831, U.S. Pat. No. 6,297,282, U.S. Pat. No.
6,239,173, U.S. Pat. No. 6,303,628, U.S. Pat. No. 6,310,079, U.S.
Pat. No. 6,300,363, U.S. Pat. No. 6,077,869, U.S. Pat. No.
6,140,515, U.S. Pat. No. 5,994,379, U.S. Pat. No. 6,028,202, U.S.
Pat. No. 6,040,320, U.S. Pat. No. 6,083,969, U.S. Pat. No.
6,306,890, U.S. Pat. No. 6,307,047, U.S. Pat. No. 6,004,948, U.S.
Pat. No. 6,169,188, U.S. Pat. No. 6,020,343, U.S. Pat. No.
5,981,576, U.S. Pat. No. 6,222,048, U.S. Pat. No. 6,057,319, U.S.
Pat. No. 6,046,236, U.S. Pat. No. 6,002,014, U.S. Pat. No.
5,945,539, U.S. Pat. No. 6,359,182, WO 97/13755, WO 96/25928, WO
96/374679, WO 95/15316, WO 95/15315, WO 96/03385, WO 95/00501, WO
94/15932, WO 95/00501, WO 94/27980, WO 96/25405, WO 96/03388, WO
96/03387, U.S. Pat. No. 5,344,991, WO 95/00501, WO 96/16934, WO
96/03392, WO 96/09304, WO 98/47890, and WO 00/24719.
[0100] The contents of any of the patent applications, and in
particular the general formulae of the therapeutically active
compounds of the claims and exemplified compounds therein, are
incorporated herein in their entirety by reference thereto.
[0101] When treating BPH, alpha-2-delta ligands may be combined
with a compound that attenuates the growth of the prostate gland.
For example, a formulation is envisaged that combines an
alpha-2-delta ligand with a human 5-.alpha. reductase inhibitory
compound [WO 95/28397].
[0102] Thus, a further aspect of the present invention is the use
of a combination of an alpha-2-delta ligand and a human 5-.alpha.
reductase inhibitory compound, or pharmaceutically acceptable salts
or solvates thereof, for the manufacture of a medicament for the
treatment of LUTS, other than urinary incontinence, associated with
BPH.
[0103] Still further there is provided a product containing an
alpha-2-delta ligand and a human 5-.alpha. reductase inhibitory
compound, or pharmaceutically acceptable salts or solvates thereof,
as a combined preparation for simultaneous, separate or sequential
use in the treatment of LUTS, other than urinary incontinence,
associated with BPH.
[0104] Preferably the LUTS is frequency.
[0105] The contents of any of the published patent applications,
and in particular the general formulae of the therapeutically
active compounds of the claims and exemplified compounds therein,
are incorporated herein in their entirety by reference thereto.
[0106] The use of the compounds and combinations described herein
may have the advantage that higher potency, longer duration of
action, fewer side effects, improved selectivity, or other more
useful properties are achieved compared to the uses of the prior
art when treating LUTS associated with OAB and/or BPH, particularly
when the LUTS is frequency.
[0107] The compounds of the present invention are prepared by
methods well known to those skilled in the art. Specifically, the
patents, patent applications and publications, mentioned
hereinabove, each of which is hereby incorporated herein by
reference, exemplify compounds which can be used in combinations,
pharmaceutical compositions, methods and kits in accordance with
the present inventions, and refer to methods of preparing those
compounds.
[0108] Pharmaceutically acceptable salts of the compounds suitable
for use in the invention include the acid addition and base salts
thereof.
[0109] Suitable acid addition salts are formed from acids which
form non-toxic salts. Examples include the acetate, aspartate,
benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate,
borate, camsylate, citrate, edisylate, esylate, formate, fumarate,
gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate,
hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide,
isethionate, lactate, malate, maleate, malonate, mesylate,
methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate,
orotate, oxalate, palmitate, pamoate, phosphate/hydrogen
phosphate/dihydrogen phosphate, saccharate, stearate, succinate,
tartrate, tosylate and trifluoroacetate salts.
[0110] Suitable base salts are formed from bases which form
non-toxic salts. Examples include the aluminium, arginine,
benzathine, calcium, choline, diethylamine, diolamine, glycine,
lysine, magnesium, meglumine, olamine, potassium, sodium,
tromethamine and zinc salts.
[0111] For a review on suitable salts, see "Handbook of
Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and
Wermuth (Wiley-VCH, Weinheim, Germany, 2002).
[0112] A pharmaceutically acceptable salt of a compound suitable
for use in the present invention may be readily prepared by mixing
together solutions of the compound and the desired acid or base, as
appropriate. The salt may precipitate from solution and be
collected by filtration or may be recovered by evaporation of the
solvent. The degree of ionisation in the salt may vary from
completely ionised to almost non-ionised.
[0113] The compounds suitable for use in the present invention may
exist in both unsolvated and solvated forms. The term `solvate` is
used herein to describe a molecular complex comprising the compound
of the invention and one or more pharmaceutically acceptable
solvent molecules, for example, ethanol. The term `hydrate` is
employed when said solvent is water.
[0114] Included within the scope of the invention are complexes
such as clathrates, drug-host inclusion complexes wherein, in
contrast to the aforementioned solvates, the drug and host are
present in stoichiometric or non-stoichiometric amounts. Also
included are complexes of the drug containing two or more organic
and/or inorganic components which may be in stoichiometric or
non-stoichiometric amounts. The resulting complexes may be ionised,
partially ionised, or non-ionised. For a review of such complexes,
see J Pharm Sci, 64 (8), 1269-1288 by Haleblian (August 1975).
[0115] Hereinafter all references to compounds suitable for use in
the present invention include references to salts, solvates and
complexes thereof and to solvates and complexes of salts
thereof.
[0116] The compounds suitable for use in the present invention
include the compounds as hereinbefore defined, polymorphs,
prodrugs, and isomers thereof (including optical, geometric and
tautomeric isomers) as hereinafter defined and
isotopically-labelled compounds.
[0117] As stated, the invention includes all polymorphs of the
compounds suitable for use in the present invention as hereinbefore
defined.
[0118] Also within the scope of the invention are so-called
`prodrugs` of the compounds suitable for use in the present
invention. Thus certain derivatives of compounds suitable for use
in the present invention which may have little or no
pharmacological activity themselves can, when administered into or
onto the body, be converted into compounds having the desired
activity, for example, by hydrolytic cleavage. Such derivatives are
referred to as `prodrugs`. Further information on the use of
prodrugs may be found in `Pro-drugs as Novel Delivery Systems, Vol.
14, ACS Symposium Series (T Higuchi and W Stella) and
`Bioreversible Carriers in Drug Design`, Pergamon Press, 1987 (ed.
E B Roche, American Pharmaceutical Association).
[0119] Prodrugs in accordance with the invention can, for example,
be produced by replacing appropriate functionalities present in the
compounds suitable for use in the present invention with certain
moieties known to those skilled in the art as `pro-moieties` as
described, for example, in "Design of Prodrugs" by H Bundgaard
(Elsevier, 1985).
[0120] Some examples of prodrugs in accordance with the invention
include: [0121] (i) where the compound contains a carboxylic acid
functionality (--COOH), an ester thereof, for example, replacement
of the hydrogen with (C.sub.1-C.sub.8)alkyl; [0122] (ii) where the
compound contains an alcohol functionality (--OH), an ether
thereof, for example, replacement of the hydrogen with
(C.sub.1-C.sub.6)alkanoyloxymethyl; and [0123] (iii) where the
compound contains a primary or secondary amino functionality
(--NH.sub.2 or --NHR where R.noteq.H), an amide thereof, for
example, replacement of one or both hydrogens with
(C.sub.1-C.sub.10)alkanoyl.
[0124] Further examples of replacement groups in accordance with
the foregoing examples and examples of other prodrug types may be
found in the aforementioned references.
[0125] Finally, certain compounds suitable for use in the present
invention may themselves act as prodrugs of other compounds
suitable for use in the present invention.
[0126] Compounds suitable for use in the present invention
containing one or more asymmetric carbon atoms can exist as two or
more stereoisomers. Where a compound contains an alkenyl or
alkenylene group, geometric cis/trans (or Z/E) isomers are
possible. Where the compound contains, for example, a keto or oxime
group or an aromatic moiety, tautomeric isomerism (`tautomerism`)
can occur. It follows that a single compound may exhibit more than
one type of isomerism.
[0127] Included within the scope of the present invention are all
stereoisomers, geometric isomers and tautomeric forms of the
compounds suitable for use in the present invention as hereinbefore
described, including compounds exhibiting more than one type of
isomerism, and mixtures of one or more thereof. Also included are
acid addition or base salts wherein the counter-ion is optically
active, for example, D-lactate or L-lysine, or racemic, for
example, DL-tartrate or DL-arginine.
[0128] The present invention includes all pharmaceutically
acceptable isotopically-labelled compounds suitable for use in the
present invention as hereinbefore described wherein one or more
atoms are replaced by atoms having the same atomic number, but an
atomic mass or mass number different from the atomic mass or mass
number usually found in nature.
[0129] Examples of isotopes suitable for inclusion in the compounds
of the invention include isotopes of hydrogen, such as .sup.2H and
.sup.3H, carbon, such as .sup.11C, .sup.13C and .sup.14C, chlorine,
such as .sup.36Cl, fluorine, such as .sup.18F, iodine, such as
.sup.123I and .sup.125I, nitrogen, such as .sup.13N and .sup.15N,
oxygen, such as .sup.15O, .sup.17O and .sup.18O, phosphorus, such
as .sup.32P, and sulphur, such as .sup.35S.
[0130] Pharmaceutically acceptable solvates in accordance with the
invention include those wherein the solvent of crystallization may
be isotopically substituted, e.g. D.sub.2O, d.sub.6-acetone,
d.sub.6-DMSO.
[0131] Compounds of the invention intended for pharmaceutical use
may be administered as crystalline or amorphous products. They may
be administered alone or in combination with one or more other
compounds of the invention or in combination with one or more other
drugs (or as any combination thereof). Generally, they will be
administered as a formulation in association with one or more
pharmaceutically acceptable excipients. The term "excipient" is
used herein to describe any ingredient other than the compound(s)
of the invention. The choice of excipient will to a large extent
depend on factors such as the particular mode of administration,
the effect of the excipient on solubility and stability, and the
nature of the dosage form.
[0132] Pharmaceutical compositions suitable for the delivery of
compounds of the present invention and methods for their
preparation will be readily apparent to those skilled in the art.
Such compositions and methods for their preparation may be found,
for example, in `Remington's Pharmaceutical Sciences`, 19th Edition
(Mack Publishing Company, 1995).
[0133] The compounds of the invention may be administered orally.
Oral administration may involve swallowing, so that the compound
enters the gastrointestinal tract, or buccal or sublingual
administration may be employed by which the compound enters the
blood stream directly from the mouth.
[0134] Formulations suitable for oral administration include solid
formulations such as tablets, capsules containing particulates,
liquids, or powders, lozenges (including liquid-filled), chews,
multi- and nano-particulates, gels, solid solution, liposome, films
(including muco-adhesive), ovules, sprays and liquid
formulations.
[0135] Liquid formulations include suspensions, solutions, syrups
and elixirs. Such formulations may be employed as fillers in soft
or hard capsules and typically comprise a carrier, for example,
water, ethanol, polyethylene glycol, propylene glycol,
methylcellulose, or a suitable oil, and one or more emulsifying
agents and/or suspending agents. Liquid formulations may also be
prepared by the reconstitution of a solid, for example, from a
sachet.
[0136] The compounds of the invention may also be used in
fast-dissolving, fast-disintegrating dosage forms such as those
described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986
by Liang and Chen (2001).
[0137] For tablet dosage forms, depending on dose, the drug may
make up from 1 wt % to 80 wt % of the dosage form, more typically
from 5 wt % to 60 wt % of the dosage form. In addition to the drug,
tablets generally contain a disintegrant. Examples of disintegrants
include sodium starch glycolate, sodium carboxymethyl cellulose,
calcium carboxymethyl cellulose, croscarmellose sodium,
crospovidone, polyvinylpyrrolidone, methyl cellulose,
microcrystalline cellulose, lower alkyl-substituted hydroxypropyl
cellulose, starch, pregelatinised starch and sodium alginate.
Generally, the disintegrant will comprise from 1 wt % to 25 wt %,
preferably from 5 wt % to 20 wt % of the dosage form.
[0138] Binders are generally used to impart cohesive qualities to a
tablet formulation. Suitable binders include microcrystalline
cellulose, gelatin, sugars, polyethylene glycol, natural and
synthetic gums, polyvinylpyrrolidone, pregelatinised starch,
hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets
may also contain diluents, such as lactose (monohydrate,
spray-dried monohydrate, anhydrous and the like), mannitol,
xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose,
starch and dibasic calcium phosphate dihydrate.
[0139] Tablets may also optionally comprise surface active agents,
such as sodium lauryl sulfate and polysorbate 80, and glidants such
as silicon dioxide and talc. When present, surface active agents
may comprise from 0.2 wt % to 5 wt % of the tablet, and glidants
may comprise from 0.2 wt % to 1 wt % of the tablet.
[0140] Tablets also generally contain lubricants such as magnesium
stearate, calcium stearate, zinc stearate, sodium stearyl fumarate,
and mixtures of magnesium stearate with sodium lauryl sulphate.
Lubricants generally comprise from 0.25 wt % to 10 wt %, preferably
from 0.5 wt % to 3 wt % of the tablet.
[0141] Other possible ingredients include anti-oxidants,
colourants, flavouring agents, preservatives and taste-masking
agents.
[0142] Exemplary tablets contain up to about 80% drug, from about
10 wt % to about 90 wt % binder, from about 0 wt % to about 85 wt %
diluent, from about 2 wt % to about 10 wt % disintegrant, and from
about 0.25 wt % to about 10 wt % lubricant.
[0143] Tablet blends may be compressed directly or by roller to
form tablets. Tablet blends or portions of blends may alternatively
be wet-, dry-, or melt-granulated, melt congealed, or extruded
before tabletting. The final formulation may comprise one or more
layers and may be coated or uncoated; it may even be
encapsulated.
[0144] The formulation of tablets is discussed in "Pharmaceutical
Dosage Forms: Tablets, Vol. 1", by H. Lieberman and L. Lachman,
Marcel Dekker, N.Y., N.Y., 1980 (ISBN 0-8247-6918-X).
[0145] Solid formulations for oral administration may be formulated
to be immediate and/or modified release. Modified release
formulations include delayed-, sustained-, pulsed-, controlled-,
targeted and programmed release.
[0146] Suitable modified release formulations for the purposes of
the invention are described in U.S. Pat. No. 6,106,864. Details of
other suitable release technologies such as high energy dispersions
and osmotic and coated particles are to be found in Verma et al,
Pharmaceutical Technology On-line, 25(2), 1-14 (2001). The use of
chewing gum to achieve controlled release is described in WO
00/35298.
[0147] The compounds of the invention may also be administered
directly into the blood stream, into muscle, or into an internal
organ. Suitable means for parenteral administration include
intravenous, intraarterial, intraperitoneal, intrathecal,
intraventricular, intraurethral, intrasternal, intracranial,
intramuscular and subcutaneous. Suitable devices for parenteral
administration include needle (including microneedle) injectors,
needle-free injectors and infusion techniques.
[0148] Parenteral formulations are typically aqueous solutions
which may contain excipients such as salts, carbohydrates and
buffering agents (preferably to a pH of from 3 to 9), but, for some
applications, they may be more suitably formulated as a sterile
non-aqueous solution or as a dried form to be used in conjunction
with a suitable vehicle such as sterile, pyrogen-free water.
[0149] The preparation of parenteral formulations under sterile
conditions, for example, by lyophilisation, may readily be
accomplished using standard pharmaceutical techniques well known to
those skilled in the art.
[0150] The solubility of compounds of the present invention used in
the preparation of parenteral solutions may be increased by the use
of appropriate formulation techniques, such as the incorporation of
solubility-enhancing agents.
[0151] Formulations for parenteral administration may be formulated
to be immediate and/or modified release. Modified release
formulations include delayed-, sustained-, pulsed-, controlled-,
targeted and programmed release. Thus compounds of the invention
may be formulated as a solid, semi-solid, or thixotropic liquid for
administration as an implanted depot providing modified release of
the active compound. Examples of such formulations include
drug-coated stents and PGLA microspheres.
[0152] The compounds of the invention may also be administered
topically to the skin or mucosa, that is, dermally or
transdermally. Typical formulations for this purpose include gels,
hydrogels, lotions, solutions, creams, ointments, dusting powders,
dressings, foams, films, skin patches, wafers, implants, sponges,
fibres, bandages and microemulsions. Liposomes may also be used.
Typical carriers include alcohol, water, mineral oil, liquid
petrolatum, white petrolatum, glycerin, polyethylene glycol and
propylene glycol. Penetration enhancers may be incorporated--see,
for example, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan
(October 1999).
[0153] Other means of topical administration include delivery by
electroporation, iontophoresis, phonophoresis, sonophoresis and
microneedle or needle-free (e.g. Powderject.TM., Bioject.TM., etc.)
injection.
[0154] Formulations for topical administration may be formulated to
be immediate and/or modified release. Modified release formulations
include delayed-, sustained-, pulsed-, controlled-, targeted and
programmed release.
[0155] The compounds of the invention can also be administered
intranasally or by inhalation, typically in the form of a dry
powder (either alone, as a mixture, for example, in a dry blend
with lactose, or as a mixed component particle, for example, mixed
with phospholipids, such as phosphatidylcholine) from a dry powder
inhaler or as an aerosol spray from a pressurised container, pump,
spray, atomiser (preferably an atomiser using electrohydrodynamics
to produce a fine mist), or nebuliser, with or without the use of a
suitable propellant, such as 1,1,1,2-tetrafluoroethane or
1,1,1,2,3,3,3-heptafluoropropane. For intranasal use, the powder
may comprise a bioadhesive agent, for example, chitosan or
cyclodextrin.
[0156] The pressurised container, pump, spray, atomizer, or
nebuliser contains a solution or suspension of the compound(s) of
the invention comprising, for example, ethanol, aqueous ethanol, or
a suitable alternative agent for dispersing, solubilising, or
extending release of the active, a propellant(s) as solvent and an
optional surfactant, such as sorbitan trioleate, oleic acid, or an
oligolactic acid.
[0157] Prior to use in a dry powder or suspension formulation, the
drug product is micronised to a size suitable for delivery by
inhalation (typically less than 5 microns). This may be achieved by
any appropriate comminuting method, such as spiral jet milling,
fluid bed jet milling, supercritical fluid processing to form
nanoparticles, high pressure homogenisation, or spray drying.
[0158] Capsules (made, for example, from gelatin or HPMC), blisters
and cartridges for use in an inhaler or insufflator may be
formulated to contain a powder mix of the compound of the
invention, a suitable powder base such as lactose or starch and a
performance modifier such as I-leucine, mannitol, or magnesium
stearate. The lactose may be anhydrous or in the form of the
monohydrate, preferably the latter. Other suitable excipients
include dextran, glucose, maltose, sorbitol, xylitol, fructose,
sucrose and trehalose.
[0159] A suitable solution formulation for use in an atomiser using
electrohydrodynamics to produce a fine mist may contain from 1
.mu.g to 20 mg of the compound of the invention per actuation and
the actuation volume may vary from 1 .mu.l to 100 .mu.l. A typical
formulation may comprise a compound of the invention, propylene
glycol, sterile water, ethanol and sodium chloride. Alternative
solvents which may be used instead of propylene glycol include
glycerol and polyethylene glycol.
[0160] Suitable flavours, such as menthol and levomenthol, or
sweeteners, such as saccharin or saccharin sodium, may be added to
those formulations of the invention intended for inhaled/intranasal
administration.
[0161] Formulations for inhaled/intranasal administration may be
formulated to be immediate and/or modified release using, for
example, poly(DL-lactic-coglycolic acid (PGLA). Modified release
formulations include delayed-, sustained-, pulsed-, controlled-,
targeted and programmed release.
[0162] The compounds of the invention may be administered rectally
or vaginally, for example, in the form of a suppository, pessary,
or enema. Cocoa butter is a traditional suppository base, but
various alternatives may be used as appropriate.
[0163] Formulations for rectal/vaginal administration may be
formulated to be immediate and/or modified release. Modified
release formulations include delayed-, sustained-, pulsed-,
controlled-, targeted and programmed release.
[0164] The compounds of the invention may also be administered
directly to the eye or ear, typically in the form of drops of a
micronised suspension or solution in isotonic, pH-adjusted, sterile
saline. Other formulations suitable for ocular and aural
administration include ointments, biodegradable (e.g. absorbable
gel sponges, collagen) and non-biodegradable (e.g. silicone)
implants, wafers, lenses and particulate or vesicular systems, such
as niosomes or liposomes. A polymer such as crossed-linked
polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic
polymer, for example, hydroxypropylmethylcellulose,
hydroxyethylcellulose, or methyl cellulose, or a
heteropolysaccharide polymer, for example, gelan gum, may be
incorporated together with a preservative, such as benzalkonium
chloride. Such formulations may also be delivered by
iontophoresis.
[0165] Formulations for ocular/aural administration may be
formulated to be immediate and/or modified release. Modified
release formulations include delayed-, sustained-, pulsed-,
controlled-, targeted, or programmed release.
[0166] The compounds of the invention may be combined with soluble
macromolecular entities, such as cyclodextrin and suitable
derivatives thereof or polyethylene glycol-containing polymers, in
order to improve their solubility, dissolution rate, taste-masking,
bioavailability and/or stability for use in any of the
aforementioned modes of administration.
[0167] Drug-cyclodextrin complexes, for example, are found to be
generally useful for most dosage forms and administration routes.
Both inclusion and non-inclusion complexes may be used. As an
alternative to direct complexation with the drug, the cyclodextrin
may be used as an auxiliary additive, i.e. as a carrier, diluent,
or solubiliser. Most commonly used for these purposes are alpha-,
beta- and gamma-cyclodextrins, examples of which may be found in WO
91/11172, WO 94/02518 and WO 98/55148.
[0168] Inasmuch as it may desirable to administer a combination of
active compounds, for example, for the purpose of treating a
particular disease or condition, it is within the scope of the
present invention that two or more pharmaceutical compositions, at
least one of which contains a compound in accordance with the
invention, may conveniently be combined in the form of a kit
suitable for co-administration of the compositions.
[0169] Thus the kit of the invention comprises two or more separate
pharmaceutical compositions, at least one of which contains a
compound as hereinbefore described in accordance with the
invention, and means for separately retaining said compositions,
such as a container, divided bottle, or divided foil packet. An
example of such a kit is the familiar blister pack used for the
packaging of tablets, capsules and the like.
[0170] The kit of the invention is particularly suitable for
administering different dosage forms, for example, oral and
parenteral, for administering the separate compositions at
different dosage intervals, or for titrating the separate
compositions against one another. To assist compliance, the kit
typically comprises directions for administration and may be
provided with a so-called memory aid.
[0171] For the avoidance of doubt, references herein to "treatment"
include references to curative, palliative and prophylactic
treatment.
CHEMISTRY EXAMPLES
Example 1
(2S,4S)-4-(3-Chloro-phenoxy)-pyrrolidine-1,2-dicarboxylic acid
1-tert-butyl Ester 2-methyl Ester
##STR00016##
[0173] To a stirred solution of
(2S,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl
ester 2-methyl ester (CAS Reg. No. 74844-91-0) (6.1 kg, 24.87 mol),
3-chlorophenol (3.52 kg, 27.39 mol) and triphenylphosphine (7.18
kg, 27.37 mol) in tert-butyl methyl ether (30.5 L) at 0.degree. C.
was added diisopropylazodicarboxylate (5.53 kg, 27.35 mol) in
tert-butyl methyl ether (15 L) dropwise. The mixture was stirred
overnight at 20.degree. C. The reaction was filtered and the
liquors washed with 0.5M sodium hydroxide (aq) (2.times.12.5 L)
& water (12.2 L). The tert-butyl methyl ether solvent was
replaced with n-heptane (42.7 L) by atmospheric pressure
distillation & cooled to crystallise crude product, which was
collected by filtration (11.1 kg, 125% contaminated with ca 35%
reduced diisopropyl dicarboxylate & triphenylphosphine
oxide--corrected yield=86%).
[0174] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.=1.46, 1.49
(2.times.s, 9H), 2.47 (2H, m), 3.71 (5H, m), 4.42 (1H, m), 4.42,
4.54 (1H, 2.times.m), 4.87 (1H, m), 6.68 (1H, m), 6.79 (1H, s),
6.92 (1H, m), 7.18 (1H, m). LRMS (Electrospray): m/z 378
(MNa.sup.+).
(2S,4S)-4-(3-Chloro-phenoxy)-pyrrolidine-1,2-dicarboxylic Acid
1-tert-butyl Ester
##STR00017##
[0176] To (2S,4S)-4-(3-chloro-phenoxy)-pyrrolidine-1,2-dicarboxylic
acid 1-tert-butyl ester 2-methyl ester (11.1 kg, 20.28 mol) in THF
(26.6 L) was added a solution of LiOH.H.sub.2O (4.86 kg, 115.4 mol)
in water (55.5 L). The mixture was stirred overnight at 25.degree.
C. The THF was removed by distillation and the resultant aqueous
solution extracted with dichloromethane (33.3 L & 16.7 L). The
combined dichloromethane layers were extracted with water (33 L
& 16.7 L). The combined aqueous phases were adjusted to pH
3-3.5 with 1 M hydrochloric acid (aq) and extracted with
dichloromethane (2.times.22.2 L). The combined dichloromethane
phases were replaced with toluene (33.3 L), which was cooled to
crystallise the product, which was collected by filtration (6.1 kg,
98%).
[0177] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.=1.42, 1.48
(2.times.s, 9H), 2.30-2.70 (m, 2H), 3.60-3.80 (m, 2H), 4.40-4.60
(m, 1H), 4.86 (m, 1H), 6.71 (m, 1H), 6.82 (m, 1H), 6.94 (m, 1H),
7.16 (m, 1H). LRMS (Electrospray): m/z [MNa.sup.+] 364, 340 [M-1]
340.
(2S,4S)-4-(3-Chloro-phenoxy)-pyrrolidine-2-carboxylic Acid
(XXVIII)
##STR00018##
[0179] A solution of
(2S,4S)-4-(3-chloro-phenoxy)-pyrrolidine-1,2-dicarboxylic acid
1-tert-butyl ester (29.25 mol) was dissolved in THF (20 L) and
filtered. To this solution was added 4M HCl in dioxane (30 L) &
stirred overnight. Tert-Butyl methyl ether (70 L) was added to the
resultant suspension & the product was collected by filtration
(7.06 kg, 86.7%).
[0180] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta.=2.65 (m, 2H),
3.60 (dd, 1H), 3.70 (d, 1H), 4.60 (dd, 1H), 5.02 (m, 1H), 6.88 (m,
1H), 6.97 (s, 1H), 7.03 (d, 1H), 7.29 (dd, 1H).
[0181] LRMS (Electrospray [MH.sup.+] 242, [M-1] 240. Microanalysis:
Found, C, 46.97; H, 4.70; N, 4.90.
C.sub.11H.sub.12ClNO.sub.3.HCl.0.1H.sub.2O requires C, 47.20; H,
4.75; N, 5.00.
Example 2
4-(3-Fluoro-benzyl)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl
Ester 2-(2-isopropyl-5-methyl-cyclohexyl) Ester
##STR00019##
[0183] 4-(3-Fluoro-benzylidene)-pyrrolidine-1,2-dicarboxylic acid
1-tert-butyl ester 2-(2-isopropyl-5-methyl-cyclohexyl) ester (1.20
g, 2.61 mmol) was dissolved in ethyl acetate:toluene (1:1, 12 ml).
The solution was submitted to hydrogenation on platinum oxide (120
mg, 10% by weight) at 25.degree. C. and 15 psi for 1 hour. The
reaction mixture was filtered through arbocel and the filtrate
reduced under pressure. The residue was purified by flashmaster
chromatography eluting with heptane:ethyl acetate (15:1) to yield
the title compound as a colourless oil (1.11 g, 91%).
[0184] .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta.=0.72-1.37 (m,
13H), 1.44 (d, 9H), 1.43-1.75 (m, 4H), 1.87-2.01 (m, 2H), 2.31-2.58
(m, 2H), 2.83 (d, 2H), 3.07 (t, 1H), 3.50-3.65 (m, 1H), 4.13-4.30
(dt, 1H), 4.71 (td, 1H), 6.90 (d, 2H), 7.00 (d, 1H), 7.30 (q, 1H).
LRMS (APCI): m/z [MH-BOC].sup.+ 362.
(2S,4S)-4-(3-Fluoro-benzyl)-pyrrolidine-2-carboxylic Acid Mono
Hydrochloride Salt (XXIX)
##STR00020##
[0186] 4-(3-Fluoro-benzyl)-pyrrolidine-1,2-dicarboxylic acid
1-tert-butyl ester 2-(2-isopropyl-5-methyl-cyclohexyl) ester (0.91
g, 1.96 mmol) was dissolved in toluene (2 ml). 6N hydrochloric acid
(50 ml) was added and stirred at reflux for 18 hr. The reaction
mixture was cooled to room temperature and extracted with ethyl
acetate (3.times.20 ml). The aqueous layer was concentrated by
evaporated under reduced pressure to give the title compound (417
mg, 81%) as a white solid. .sup.1H-NMR showed a 7:1 ratio of
cis:trans diastereoisomers so the product was recrystallised from
isopropyl alcohol to give the title compound (170 mg, 65%) in a
ratio of 14:1 cis:trans as determined by NMR.
[0187] .sup.1H-NMR (400 MHz, CD.sub.3OD): (mixture of
diastereoisomers 2S,4S:2S,4R (14:1)): .delta.=1.85 (q, 1H), 2.51
(quin, 1H), 2.69-2.85 (m, 3H), 3.07 (t, 1H), 3.41 (dd, 1H), 4.38
and 4.48 (t, 1H), 6.90-7.04 (m, 3H), 7.32 (q, 1H). LRMS (APCI): m/z
[MH].sup.+ 224. [.alpha.].sub.D.sup.25-1.27.degree. (c=9.00 in
methanol). Microanalysis. Found C, 55.56; H, 5.81; N, 5.34%.
C.sub.12H.sub.14FNO.sub.2.HCl requires C, 55.50; H, 5.82; N,
5.39%.
Example 3
4-(3-Fluoro-benzyl)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl
Ester 2-(2-isopropyl-5-methyl-cyclohexyl) Ester
##STR00021##
[0189] 4-(3-Fluoro-benzyl)-pyrrolidine-1,2-dicarboxylic acid
1-tert-butyl ester 2-(2-isopropyl-5-methyl-cyclohexyl) ester was
prepared by a method analogous to that for the preparation of
4-(3-fluoro-benzyl)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl
ester 2-(2-isopropyl-5-methyl-cyclohexyl) ester, using the
appropriate starting alkenic menthol ester; [MH] 480. Microanalysis
(mixture of diastereoisomers cis (major) and trans): Found: C,
67.74; H, 8.30; N, 2.90%. C.sub.27H.sub.39F.sub.2NO.sub.4. requires
C, 67.62; H, 8.20; N, 2.92%. [.alpha.].sub.D.sup.25-71.92.degree.
(c=3.26 in methanol)
(2S,4S)-4-(2,3-Difluoro-benzyl)-pyrrolidine-2-carboxylic Acid
mono-hydrochloride Salt (XXX)
##STR00022##
[0190] The title compound was made by the method of example 2,
starting from 4-(3-fluoro-benzyl)-pyrrolidine-1,2-dicarboxylic acid
1-tert-butyl ester 2-(2-isopropyl-5-methyl-cyclohexyl) ester, and
purified by re-crystallisation with acetone/ether to give the title
compound as a mixture of diastereoisomers (2S,4S:2S,4R (12:1))
determined by .sup.1H-NMR (500 mg, 60%) as a white solid.
[0191] .sup.1H-NMR (400 MHz, CD.sub.3OD) (mixture of
diastereoisomers cis:trans (12:1)): .delta.=0.80-1.90 (m, 0.92H),
2.12-2.20 (m, 0.08H), 2.28-2.36 (m, 0.08H), 2.49-2.58 (q, 0.92H),
2.66-2.81 (m, 1H), 2.83-2.95 (m, 2H), 3.02-3.13 (t, 1H), 3.46 (dd,
1H), 4.40 (dd, 0.92H), 4.48-4.54 (m, 0.08H), 7.03-7.20 (m, 3H).
LRMS (Electrospray): m/z [M+H].sup.+ 242. Microanalysis. Found C,
51.42; H, 5.08; N, 5.01%. C.sub.12H.sub.13NO.sub.2F.sub.2.HCl
requires C, 51.90; H, 5.08; N, 5.04%.
Example 4
(2S,4S)-Pyrrolidine-1,2,4-tricarboxylic Acid 1,2-di-tert-butyl
Ester
##STR00023##
[0193] To a mixture of 4-phenyl-pyrrolidine-1,2-dicarboxylic acid
di-tert-butyl ester (CAS Reg. No. 344 286-69-7; J. Org. Chem.,
2001, 3593-3596) (0.78 g, 2.24 mmol) and sodium periodate (5.77 g,
27 mmol) stirring at 0.degree. C. under a nitrogen atmosphere in
ethyl acetate (5.5 ml), acetonitrile (5.5 ml) and water (8.5 ml)
was added ruthenium trichloride (10 mg, 0.05 mmol) and stirred to
room temperature over 18 hours. Diethyl ether (20 ml) was added and
stirred for a further 1 hr. 1 M hydrochloric acid (5 ml) was added
and the mixture extracted with ethyl acetate (3.times.30 ml).
Organic extracts were combined, dried (MgSO.sub.4), filtered and
evaporated under reduced pressure. The residue was purified by
chromatography on silica gel, eluting with 50:50:1 ethyl
acetate:heptane:glacial acetic acid to give the title compound as a
colourless gum (501 mg, 78%)
[0194] .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta.=1.40-1.49 (m,
18H); 2.26-2.40 (m, 1H); 2.42-2.56 (m, 1H); 3.02-3.12 (m, 1H);
3.65-3.80 (m, 1.4H) & 3.80-3.88 (m, 0.6H) [rotamers]; 4.09-4.20
(m, 0.7H) & 4.20-4.26 (m, 0.3H) [rotamers]. LRMS
(electrospray): [M-1] 314
(2S,4S)-4-(3-fluoro-phenoxymethyl)-pyrrolidine-2-carboxylic Acid
(XXI)
##STR00024##
[0196] 4-(3-Fluoro-phenoxymethyl)-pyrroline-1,2-dicarboxylic acid
di-tert-butyl ester (475 mg, 1.2 mmol) was dissolved in a solution
of anhydrous hydrogen chloride in dioxane (4M, 15 ml) and stirred
at 50.degree. C. under a nitrogen atmosphere for 1 hour. The
solvent was removed under reduced pressure and the resulting
semi-solid triturated with ethyl acetate to give a white solid
which was recrystallised from ethyl acetate/isopropyl alcohol to
give the title compound as a mixture of diastereomers (.about.5:1
2S,4S:2S,4R) as a white solid hydrochloride salt (90 mg, 35%).
[0197] .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta.=2.04-2.09 (m,
0.8H); 2.33-2.47 (m, 0.4H); 2.65-2.75 (m, 0.8H); 2.88-3.00 (m, 1H);
3.33-3.40 (m, 1H); 3.52-3.60 (m, 0.8H); 3.60-3.68 (0.2H); 3.96-4.04
(m, 1H); 4.04-4.12 (m, 1H); 4.42-4.51 (m, 0.8H); 4.40-4.56 (m,
0.2H); 6.65-6.80 (m, 3H), 7.21-7.30 (m, 1H). LRMS (electrospray):
[M+1] 240; [M+23] 262; [M-1] 238.
Example 5
(3S,5R)-3-Amino-5-methyl-octanoic Acid
hydrochloride(R)-2,6-Dimethyl-non-2-ene
[0198] To (S)-citronellyl bromide (50 g, 0.228 mol) in THF (800 mL)
at 0.degree. C. was added LiCl (4.3 g) followed by CuCl.sub.2 (6.8
g). After 30 minutes methylmagnesium chloride (152 mL of a 3 M
solution in THF, Aldrich) was added and the solution warmed to room
temperature. After 10 hours the solution was cooled to 0.degree. C.
and a saturated aqueous solution of ammonium chloride carefully
added. The resultant two layers were separated and the aqueous
phase extracted with ether. The combined organic phases were dried
(MgSO.sub.4) and concentrated to give (R)-2,6-dimethyl-non-2-ene.
32.6 g; 93%. Used without further purification. .sup.1H NMR (400
MHz; CDCl.sub.3) .delta. 5.1 (m, 1H), 1.95 (m, 2H), 1.62 (s, 3H),
1.6 (s, 3H), 1.3 (m, 4H), 1.2 (m, 2H), 0.8 (s, 6H).
(R)-4-Methyl-heptanoic Acid
[0199] To (R)-2,6-dimethyl-non-2-ene (20 g, 0.13 mol) in acetone
(433 mL) was added a solution of CrO.sub.3 (39 g, 0.39 mol) in
H.sub.2SO.sub.4 (33 mL)/H.sub.2O (146 mL) over 50 minutes. After 6
hours a further amount of CrO.sub.3 (26 g, 0.26 mol) in
H.sub.2SO.sub.4 (22 mL)/H.sub.2O (100 mL) was added. After 12 hours
the solution was diluted with brine and the solution extracted with
ether. The combined organic phases were dried (MgSO.sub.4) and
concentrated. Flash chromatography (gradient of 6:1 to 2:1
hexane/EtOAc) gave (R)-4-methyl-heptanoic acid as an oil. 12.1 g;
65%. MS, m/z (relative intensity): 143 [M-H, 100%].
(4R,5S)-4-Methyl-3-((R)-4-methyl-heptanoyl)-5-phenyl-oxazolidin-2-one
[0200] To (R)-4-methyl-heptanoic acid (19 g, 0.132 mol) and
triethylamine (49.9 g, 0.494 mol) in THF (500 mL) at 0.degree. C.
was added trimethylacetylchloride (20 g, 0.17 mol). After 1 hour
LiCl (7.1 g, 0.17 mol) was added followed by
(4R,5S)-(+)-4-methyl-5-phenyl-2-oxazolidinone) 3 (30 g, 0.17 mol).
The mixture was warmed to room temperature and after 16 hours the
filtrate was removed by filtration and the solution concentrated
under reduced pressure. Flash chromatography (7:1 hexane/EtOAc)
gave
(4R,5S)-4-methyl-3-((R)-4-methyl-heptanoyl)-5-phenyl-oxazolidin-2-one
as an oil. 31.5 g; 79%. [.alpha.].sub.D=+5.5 (c 1 in CHCl.sub.3).
MS, m/z (relative intensity): 304 [M+H, 100%].
(3S,5R)-5-Methyl-3-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl-
)-octanoic Acid tert-butyl Ester
[0201] To
(4R,5S)-4-methyl-3-((R)-4-methyl-heptanoyl)-5-phenyl-oxazolidin--
2-one (12.1 g, 0.04 mol) in THF (200 ml) at -50.degree. C. was
added sodium bis(trimethylsilyl)amide (48 mL of a 1 M solution in
THF). After 30 min t-butylbromoaceate (15.6 g, 0.08 mol) was added.
The solution was stirred for 4 hours at -50.degree. C. and then
warmed to room temperature. After 16 hours a saturated aqueous
solution of ammonium chloride was added and the two layers
separated. The aqueous phase was extracted with ether and the
combined organic phases dried (MgSO.sub.4) and concentrated. Flash
chromatography (9:1 hexane/EtOAc) gave
(3S,5R)-5-methyl-3-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbony-
l)-octanoic acid tert-butyl ester as a white solid 12 g; 72%.
[.alpha.].sub.D=+30.2 (c 1 in CHCl.sub.3). .sup.13C NMR (100 MHz;
CDCl.sub.3) .delta. 176.47, 171.24, 152.72, 133.63, 128.87, 125.86,
80.85, 78.88, 55.34, 39.98, 38.77, 38.15, 37.58, 30.60, 28.23,
20.38, 20.13, 14.50, 14.28.
(S)-2-((R)-2-Methyl-pentyl)-succinic Acid 4-tert-butyl Ester
[0202] To
(3S,5R)-5-methyl-3-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidine--
3-carbonyl)-octanoic acid tert-butyl ester (10.8 g, 0.025 mol) in
H.sub.2O (73 mL) and THF (244 mL) at 0.degree. C. was added a
premixed solution of LiOH (51.2 mL of a 0.8 M solution) and
H.sub.2O.sub.2 (14.6 mL of a 30% solution). After 4 hours a further
12.8 mL LiOH (0.8 M solution) and 3.65 mL of H.sub.2O.sub.2 (30%
solution) was added. After 30 minutes sodium bisulfite (7 g),
sodium sulfite (13 g), and water (60 mL) was added followed by
hexane (100 mL) and ether (100 mL). The two layers were separated
and the aqueous layer extracted with ether. The combined organic
phases were concentrated to an oil that was dissolved in heptane
(300 mL). The resultant solid was filtered off and the filtrate
dried (MgSO.sub.4) and concentrated to afford
(S)-2-((R)-2-methyl-pentyl)-succinic acid 4-tert-butyl ester (6 g,
93%) which was used immediately without further purification. MS,
m/z (relative intensity): 257 [M+H, 100%].
(3S,5R)-3-Benzyoxycarbonylamino-5-methyl-octanoic Acid, tert-butyl
Ester
[0203] A solution of (S)-2-((R)-2-methyl-pentyl)-succinic acid
4-tert-butyl ester (6.0 g, 23.22 mmol) and triethylamine (3.64 mL,
26.19 mmol) in toluene (200 mL) was treated with diphenylphosphoryl
azide (5.0 mL, 23.22 mL) and stirred at room temperature for 0.5
hours. After the reaction mixture was then heated at reflux for 3 h
and cooled briefly, benzyl alcohol was added (7.2 mL, 69.7 mmol)
and the solution heated for another 3 h. After the reaction mixture
was allowed to cool, it was diluted with ethyl ether (200 mL) and
the combined organic layer was washed successively with saturated
NaHCO.sub.3 and brine and dried (Na.sub.2SO.sub.4). The
concentrated organic component was purified by chromatography
(MPLC) eluting with 8:1 hexanes:ethyl acetate to provide
(3S,5R)-3-benzyoxycarbonylamino-5-methyl-octanoic acid, tert-butyl
ester (6.4 g, 75.8%). MS: M+1: 364.2, 308.2.
(3S,5R)-3-Amino-5-methyl-octanoic Acid, tert-butyl Ester
[0204] A solution of
(3S,5R)-3-benzyoxycarbonylamino-5-methyl-octanoic acid, tert-butyl
ester (2.14 g, 5.88 mmol) in THF (50 mL) was treated with Pd/C (0.2
g) and H.sub.2 at 50 psi for 2 hours. The reaction mixture was then
filtered and concentrated to an oil in vacuo to give
(3S,5R)-3-amino-5-methyl-octanoic acid, tert-butyl ester in
quantitative yield. MS: M+1:230.2, 174.1.
(3S,5R)-3-Amino-5-methyl-octanoic Acid Hydrochloride
[0205] A slurry of (3S,5R)-amino-5-methyl-octanoic acid, tert-butyl
ester (2.59 g, 11.3 mmol) in 6N HCl (100 mL) was heated under
reflux 18 hours, cooled, and filtered over Celite. The filtrate was
concentrated in vacuo to 25 mL and the resulting crystals were
collected and dried to provide (3S,5R)-3-amino-5-methyl-octanoic
acid hydrochloride, mp 142.5-142.7.degree. C. (1.2 g, 50.56%). A
second crop (0.91 g) was obtained from the filtrate. Anal. Calc'd
for C.sub.9H.sub.19NO.sub.2.HCl: C, 51.55; H, 9.61; N, 6.68, Cl:
16.91. Found: C, 51.69; H, 9.72; N, 6.56, Cl: 16.63.
(3S,5R)-3-Amino-5-methyl-octanoic Acid Hydrochloride Acid Salt
[0206] 5.3 g of 2S-(2R-methyl-pentyl)-succinic acid-4-tert-butyl
ester contained in 30 mL methyltertbutyl ether is reacted at room
temperature with 3.5 mL triethylamine followed by 6.4 g of
diphenylphosphoryl azide. After allowing the reaction to exotherm
to 45.degree. C. and stirring for at least 4 hours, the reaction
mixture is allowed to cool to room temperature and stand while the
phases separated. The lower layer is discarded and the upper layer
is washed with water, followed by dilute aqueous HCl. The upper
layer is then combined with 10 mL of 6 N aqueous HCl, and stirred
at 45-65.degree. C. The reaction mixture is concentrated by vacuum
distillation to about 10-14 mL and allowed to crystallize while
cooling to about 5.degree. C. After collecting the product by
filtration, the product is washed with toluene and reslurried in
toluene. The product is dried by heating under vacuum resulting in
2.9 g (67%) of white crystalline product. The product may be
recrystallized from aqueous HCl. mp 137.degree. C.
Example 6
Methanesulfonic Acid (S)-3,7-dimethyl-oct-6-enyl Ester
[0207] To S-(-)-citronellol (42.8 g, 0.274 mol) and triethylamine
(91 mL, 0.657 mol) in CH.sub.2Cl.sub.2 (800 mL) at 0.degree. C. was
added methanesulphonyl chloride (26 mL, 0.329 mol) in
CH.sub.2Cl.sub.2 (200 mL). After 2 hours at 0.degree. C. the
solution was washed with 1N HCl then brine. The organic phase was
dried (MgSO.sub.4) and concentrated to afford the titled compound
an oil (60.5 g, 94%) which was used without further purification.
MS, m/z (relative intensity): 139 [100%], 143 [100%].
(R)-2,6-Dimethyl-oct-2-ene
[0208] To methanesulfonic acid (S)-3,7-dimethyl-oct-6-enyl ester
(60 g, 0.256 mol) in THF (1 L) at 0.degree. C. was added lithium
aluminium hydride (3.8 g, 0.128 mol). After 7 hours, a further 3.8
g of lithium aluminum hydride was added and the solution warmed to
room temperature. After 18 hours, a further 3.8 g of lithium
aluminum hydride was added. After a further 21 hours, the reaction
was carefully quenched with 1N citric acid and the solution diluted
further with brine. The resultant two phases were separated and the
organic phase was dried (MgSO.sub.4) and concentrated to afford the
titled compound as an oil which was used without further
purification. MS, m/z (relative intensity): 139 [M+H, 100%].
(R)-4-Methyl-hexanoic Acid
[0209] A procedure similar to the synthesis of
(R)-4-methyl-heptanoic acid was utilized giving the acid as an oil
(9.3 g, 56%). MS, m/z (relative intensity): 129 [M-H, 100%].
(4R,5S)-4-Methyl-3-((R)-4-methyl-hexanoyl)-5-phenyl-oxazolidin-2-one
[0210] A procedure similar to the synthesis of
(4R,5S)-4-methyl-3-((R)-4-methyl-heptanoyl)-5-phenyl-oxazolidin-2-one
was utilized giving the titled compound as an oil (35.7 g, 95%).
MS, m/z (relative intensity): 290 [M+H, 100.
(3S,5R)-5-Methyl-3-[1-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-yl)-me-
thanoyl]-heptanoic Acid tert-butyl Ester
[0211] A procedure similar to the preparation of
(3S,5R)-5-methyl-3-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbony-
l)-octanoic acid tert-butyl ester was followed giving the titled
compound as an oil (7.48 g; 31%). MS, m/z (relative intensity): 178
[100%], 169 [100%]; [.alpha.].sub.D=+21.6 (c 1 in CHCl.sub.3).
(S)-2-((R)-2-Methyl-butyl)-succinic acid 4-tert-butyl Ester
[0212]
(3S,5R)-5-Methyl-3-[1-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-
-yl)-methanoyl]-heptanoic acid tert-butyl ester (7.26 g, 0.018 mol)
in H.sub.2O (53 mL) and THF (176 mL) at 0.degree. C. was added a
premixed solution of LiOH (37 mL of a 0.8 M solution) and
H.sub.2O.sub.2 (10.57 mL of a 30% solution) and the solution warmed
to room temperature. After 2 hours sodium bisulfite (7 g), sodium
sulfite (13 g), and water (60 mL) was added and the two layers were
separated and the aqueous layer extracted with ether. The combined
organic phases were concentrated to an oil that was dissolved in
heptane (200 mL). The resultant solid was filtered off and the
filtrate dried (MgSO.sub.4) and concentrated to afford the titled
compound as an oil (4.4 g) that was used without further
purification. MS, m/z (relative intensity): 243 [100%].
(3S,5R)-3-Benzyoxycarbonylamino-5-methyl-heptanoic Acid, tert-butyl
Ester
[0213] This compound was prepared as described above starting with
(S)-2-((R)-2-methyl-butyl) succinic acid, 4-tert-butyl ester to
give (3S,5R)-3-benzyoxycarbonylamino-5-methyl-heptanoic acid,
tert-butyl ester as an oil (73.3% yield). .sup.1H NMR (400 MHz;
CDCl.sub.3) .delta. 0.84 (t, 3H, J=7.33 Hz), 0.89 (d, 3H, J=6.60
Hz), 1.12-1.38 (m, 4H), 1.41 (s, 9H), 1.43-1.59 (m, 2H), 2.42 (m,
2H), 4.05 (m, 1H), 5.07 (t, 2H J=12.95 Hz), and 7.28-7.34 (m,
5H).
(3S,5R)-Amino-5-methyl-heptanoic Acid, tert-butyl Ester
[0214] This compound was prepared as described above starting with
(3S,5R)-3-benzyoxycarbonylamino-5-methyl-heptanoic acid, tert-butyl
ester instead of (3S,5R)-3-benzyoxycarbonylamino-5-methyl-octanoic
acid, tert-butyl ester to give the titled compound. .sup.1H NMR
(400 MHz; CDCl.sub.3) .delta. 0.84 (overlapping t and d, 6H),
1.08-1.16 (m, 2H), 1.27-1.30 (m, 2H), 1.42 (s, 9H), 1.62 (br s,
2H), 2.15 (dd, 1H, J=8.54 and 15.62 Hz), 2.29 (dd, 1H, J=4.15 and
15.37 Hz), and 3.20 (br s, 2H).
(3S,5R)-Amino-5-methyl-heptanoic Acid Hydrochloride
[0215] A slurry of (3S,5R)-amino-5-methyl-heptanoic acid,
tert-butyl ester (1.44 g, 6.69 mmol) in 3N HCl was heated at reflux
for 3 hours, filtered hot over Celite, and concentrated to dryness.
Trituration of the resulting solid in ethyl ether provided
(3S,5R)-3-amino-5-methyl-heptanoic acid hydrochloride, (0.95 g,
85%) mp 126.3-128.3.degree. C.
Example 7
(3S,5R)-3-Amino-5-methyl-nonanoic Acid
[0216] (R)-4-Methyl-octanoic acid. Lithium chloride (0.39 g, 9.12
mmol) and copper (I) chloride (0.61 g, 4.56 mmol) were combined in
45 ml THF at ambient temperature and stirred 15 minutes, then
cooled to 0.degree. C. at which time ethylmagnesium bromide (1 M
solution in THF, 45 mL, 45 mmol) was added. (S)-citronellyl bromide
(5.0 g, 22.8 mmol) was added dropwise and the solution was allowed
to warm slowly to ambient temperature with stirring overnight. The
reaction was quenched by cautious addition of sat. NH.sub.4Cl (aq),
and stirred with Et.sub.2O and sat. NH.sub.4Cl (aq) for 30 minutes.
The phases were separated and the organic phase dried (MgSO.sub.4)
and concentrated. The crude (R)-2,6-dimethyl-dec-2-ene was used
without purification. To a solution of (R)-2,6-dimethyl-dec-2-ene
(3.8 g, 22.8 mmol) in 50 mL acetone at 0.degree. C. was added
Jones' reagent (2.7 M in H.sub.2SO.sub.4 (aq), 40 mL, 108 mmol) and
the solution was allowed to warm slowly to ambient temperature with
stirring overnight. The mixture was partitioned between Et.sub.2O
and H.sub.2O, the phases were separated, and the organic phase
washed with brine, dried (MgSO.sub.4), and concentrated. The
residue was purified by flash chromatography (8:1 hexanes:EtOAc) to
afford 2.14 g (59%) of the titled compound as a colourless oil:
LRMS: m/z 156.9 (M.sup.+). Jones' reagent was prepared as a 2.7M
solution by combining 26.7 g CrO.sub.3, 23 mL H.sub.2SO.sub.4, and
diluting to 100 mL with H.sub.2O.
(4R,5S)-4-Methyl-3-((R)-4-methyl-octanoyl)-5-phenyl-oxazolidin-2-one
[0217] To (R)-4-methyl-octanoic acid (2.14 g, 13.5 mmol) in 25 mL
CH.sub.2Cl.sub.2 at 0.degree. C. was added 3 drops DMF, followed by
oxalyl chloride (1.42 mL, 16.2 mmol) resulting in vigorous gas
evolution. The solution was warmed directly to ambient temperature,
stirred 30 minutes, and concentrated. Meanwhile, to a solution of
the oxazolidinone (2.64 g, 14.9 mmol) in 40 mL THF at -78.degree.
C. was added n-butyllithium (1.6 M soln in hexanes, 9.3 mL, 14.9
mmol) dropwise. The mixture was stirred for 10 minutes at which
time the acid chloride in 10 mL THF was added dropwise. The
reaction was stirred 30 minutes at -78.degree. C., then warmed
directly to ambient temperature and quenched with sat. NH.sub.4Cl.
The mixture was partitioned between Et.sub.2O and sat. NH.sub.4Cl
(aq), the phases were separated, and the organic phase dried
(MgSO.sub.4), and concentrated to furnish 3.2 g of the titled
compound as a colourless oil. LRMS: m/z 318.2 (M+).
(3S,5R)-5-Methyl-3-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl-
)-nonanoic Acid tert-butyl Ester
[0218] To a solution of diisopropylamine (1.8 mL, 12.6 mmol) in 30
mL THF at -78.degree. C. was added n-butyllithium (1.6 M soln in
hexanes, 7.6 mL, 12.1 mmol), and the mixture stirred 10 minutes at
which time
(4R,5S)-4-Methyl-3-((R)-4-methyl-octanoyl)-5-phenyl-oxazolidin-2-one
(3.2 g, 10.1 mmol) in 10 mL THF was added dropwise. The solution
was stirred for 30 minutes, t-butyl bromoacetate (1.8 mL, 12.1
mmol) was added quickly dropwise at -50.degree. C., and the mixture
was allowed to warm slowly to 10.degree. C. over 3 hours. The
mixture was partitioned between Et.sub.2O and sat. NH.sub.4Cl (aq),
the phases were separated, and the organic phase dried
(MgSO.sub.4), and concentrated. The residue was purified by flash
chromatography (16:1 to 8:1 hexanes:EtOAc) to provide 2.65 g (61%)
of the titled compound as a colourless crystalline solid,
mp=84-86.degree. C. [.delta.].sub.D.sup.23+17.1 (c=1.00,
CHCl.sub.3).
(S)-2-((R)-2-Methyl-hexyl)-succinic acid 4-tert-butyl Ester
[0219] To a solution of
(3S,5R)-5-Methyl-3-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbony-
l)-nonanoic acid tert-butyl ester (2.65 g, 6.14 mmol) in 20 mL THF
at 0.degree. C. was added a precooled (0.degree. C.) solution of
LiOH monohydrate (1.0 g, 23.8 mmol) and hydrogen peroxide (30 wt %
aqueous soln, 5.0 mL) in 10 mL H.sub.2O. The mixture was stirred
vigorously for 90 minutes, then warmed to ambient temperature and
stirred 90 minutes. The reaction was quenched at 0.degree. C. by
addition of 100 mL 10% NaHSO.sub.3 (aq), then extracted with
Et.sub.2O. The phases were separated, and the organic phase washed
with brine, dried (MgSO.sub.4), and concentrated. The titled
compound was used without purification.
(3S,5R)-3-Benzyoxycarbonylamino-5-methylnonanoic Acid, tert-butyl
Ester
[0220] This compound was prepared similarly as described above
starting with (S)-2-((R)-2-methylhexyl) succinic acid, 4-tert-butyl
ester instead of (S)-2-((R)-2-methylpentyl) succinic acid,
4-tert-butyl ester to provide the titled compound as an oil (71.6%
yield). .sup.1HNMR (400 MHz; CDCl.sub.3) .delta. 0.81 (t, 3H,
J=4.40 Hz), 0.85 (d, 3H, J=6.55 Hz), 1.06-1.20 (m, 7H), 1.36 (s,
9H), 1.38-1.50 (m, 2H), 2.36 (m, 2H), 3.99 (m, 1H), 5.02 (m+s, 3H),
and 7.28-7.28 (m, 5H).
(3S,5R)-3-Amino-5-methyl-nonanoic Acid, tert-butyl Ester
[0221] This compound was prepared as described above starting with
(3S,5R)-benzyoxycarbonylamino-5-methyl-nonanoic acid, tert-butyl
ester instead of (3S,5R)-3-benzyoxycarbonylamino-5-methyl-octanoic
acid, tert-butyl ester. Yield=97%. .sup.1H NMR (400 MHz;
CDCl.sub.3) .delta. 0.82 (overlapping d and t, 6H), 1.02-1.08 (m,
1H), 1.09-1.36 (m, 6H), 1.39 (s, 9H), 1.47 (br s, 1H), 1.80 (s,
2H), 2.13 (dd, 1H, J=8.54 and 15.61 Hz), and 2.27 (dd, 1H, J=4.15
and 15.38 Hz).
(3S,5R)-3-Amino-5-methyl-nonanoic Acid Hydrochloride
[0222] A mixture of (3S,5R)-3-amino-5-methyl-nonanoic acid,
tert-butyl ester (1.50 g, 6.16 mmol) in 3N HCl (100 mL) was heated
at reflux for 3 hours, filtered hot over Celite, and concentrated
to 30 mL in vacuo. The resulting crystals were collected, washed
with additional 3N HCl, and dried to provide the title compound, mp
142.5-143.3.degree. C. Additional crops were obtained from the
filtrate to provide 1.03 g (70.4%). Anal. Calc'd for
C.sub.10H.sub.21NO.sub.2HCl: C, 53.68; H, 9.91; N, 6.26, Cl: 15.85.
Found: C, 53.89; H, 10.11; N, 6.13. MS: M+1: 188.1.
BIOLOGY EXAMPLES
[0223] The biological activity of compounds suitable for use in the
invention as alpha-2-delta ligands may be measured in a radioligand
binding assay using [.sup.3H]gabapentin and the .alpha.-2-.delta.
subunit derived from porcine brain tissues (Gee N. S., Brown J. P.,
Dissanayake V. U. K., Offord J., Thurlow R., Woodruff G. N., J.
Biol. Chem., 1996; 271:5879-5776).
Example 1
Investigation into the Effects of an Alpha-2-Delta Ligand on the
Micturition Reflex of Anaesthetised Rats
1.0 Material and Methods:
Animals
[0224] Four caesarean derived (CD) rats weighing approximately 225
g were anaesthetised using urethane and continuous cystometry
performed.
[0225] The animals were anaesthetised using urethane (1.2 g/kg,
i.p.). Depth of anaesthesia was assessed by the stability of blood
pressure and heart rate, and by an absence of hind limb withdrawal
in response to paw pinch. Supplementary doses of urethane (0.1 g
kg-1, i.v.) were given where necessary.
[0226] The trachea was intubated to maintain a patent airway, an
external jugular vein was cannulated for drug administration, and a
common carotid artery was cannulated with a heparinised cannula (20
units/ml heparin in 0.9% w/v saline) for the measurement of
arterial blood pressure.
[0227] Blood pressure was measured using a pressure transducer and
the heart rate (HR) derived electronically on-line from the blood
pressure using PoneMah (Linton Pty Ltd UK). Body temperature was
monitored with a rectal temperature probe and maintained between
36-38.degree. C. using a homeothermic blanket system (Harvard, UK).
Animals were allowed to breathe air spontaneously throughout the
duration of the experiment.
[0228] The urinary bladder was exposed by a midline abdominal
incision. A cannula (c. 0.52 mm internal and 1.2 mm external
diameter) was inserted into the bladder dome as a means of infusing
the bladder while simultaneously recording intravesical bladder
pressure. The bladder was infused with physiological saline (0.9%)
at the rate of 0.046 ml/min, to simulate the maximal hourly
diuresis rate of the rat (Klevmark B [1974]--Motility of the
urinary bladder in cats during filling at physiological rates. I.
Intravesical pressure patterns studied by a new method of
cystometry. Acta Physiol Scand 90(3): 565-77).
[0229] Following the surgical procedure the animals were allowed to
stabilise for c. 30 min. After the stabilisation period, cystometry
was performed and bladder function (interval between micturition)
in response to Gabapentin-HCl (0.3, 1, 3 and 10 mg/kg administered
intravenously) was monitored.
Statistical Analysis
[0230] Differences between treatment groups were examined using
ANOVA.
Compound
[0231] Gabapentin-HCl (Tocris, UK) was dissolved in saline.
2.0 Results:
Time Interval Between Voiding Episodes
[0232] The interval between voiding events was increased in
response to gabapentin (see FIG. 1) relative to corresponding
control periods. It was observed from the study that gabapentin
significantly extended the interval between voiding events in a
dose dependent manner. Indeed, 10 mg/kg of gabapentin administered
intravenously significantly prolonged the micturition interval
relative to corresponding control animals (3.1.+-.0.29 v
9.89.+-.2.72 min P<0.05). As a consequence of improving the
interval between micturition events bladder capacity was improved
significantly by 200% in response to gabapentin. It is interesting
to note that gabapentin, when administered at 10 mg/kg, did not
have any adverse effects on micturition efficiency, urine retention
or bladder contraction upon voiding.
[0233] Thus it is demonstrated that administration of an
alpha-2-delta ligand increases bladder capacity and reduces the
LUTS in female animals, indicating the utility of such an approach
in treating the LUTS associated with OAB.
Example 2
Effect of an Alpha-2-Delta Ligand on Micturition Frequency and
Bladder Pressure in the Male Spontaneously Hypertensive Rat
(SHR)
1.0 Materials and Methods:
[0234] Eight (8) male spontaneously hypertensive rats were prepared
surgically with Data Sciences International (DSI) telemetry
transponders (TL11M2-C50-PXT). Bladder pressure was continuously
monitored with the aid of a pressure catheter placed via the dome
of the bladder.
[0235] Bladder parameters (bladder pressure, voiding pressure and
the number of voids) were recorded in response to placebo or
treatment with 60 mg/kg Gabapentin administered subcutaneously
(s/c).
2.0 Results:
[0236] As depicted in FIG. 2, Gabapentin at 60 mg/kg s/c
significantly decreased (P<0.05) micturition interval and hence
increased bladder capacity. Moreover, and importantly for lower
urinary tract symptoms (LUTS), average bladder pressure during the
filling stages of the micturition cycle were significantly
decreased (P<0.05) in response to Gabapentin relative to
corresponding control periods (see FIG. 3).
[0237] Thus it is demonstrated that administration of an
alpha-2-delta ligand increases bladder capacity and reduces the
LUTS in male animals, indicating the utility of such an approach in
treating the LUTS associated with BPH.
* * * * *